Depressive disorders. Etiology pathogenesis of depression

MONOAMINE METABOLISM DISORDER

As noted in the previous chapter, the polyetiology of endogenous depression indicates the presence of some common links in the pathogenesis of this disease. Currently, the so-called monoamine hypothesis of the pathogenesis of depression is most widely accepted. It comes down to the fact that with endogenous depression there is a deficiency of norepinephrine and (or) serotonin in the brain (Schiedkraut J., 1965; Coppen A 1967; Lapin I.P., Oksenkrug G.F., 19G9).

As is known, norepinephrine and serotonin act as mediators in the central nervous system and, most importantly, in those parts of the brain that are involved in the formation of emotions, instinctive behavior, impulses, as well as autonomic and neuroendocrine regulation. The cell bodies of monoaminergic neurons are located in upper sections brain stem and midbrain, and their axons reach the nuclei of the limbic system, hypothalamus, lower parts of the brain stem, cerebellar cortex and neocortex. Thus, the synaptic endings of the processes of these neurons interact with the main functional areas of the brain. Considering that each neuron has many thousands of synaptic endings, a complex of monoaminergic neurons can carry out the most complex integrative processes.

Norepinephrine is synthesized in neurons from tyrosine, the precursor of which is phenylalanine. Tyrosine is converted to dioxyphenylalanine (DOPA) under the influence of tyrosine hydroxylase. By decarboxylation, DOPA is converted to dopamine, which in turn is converted to norepinephrine by dopamine beta-hydroxylase. Norepinephrine accumulates in the presynaptic terminal in granules, of which, under the influence nerve impulse he is thrown into synaptic cleft and, interacting with the receptors of the postsynaptic ending, transmits the nerve impulse to the next neuron. In the synaptic cleft, the destruction of norepinephrine is carried out by catecholomethyltransferase. A significant part of the undegraded transmitter penetrates through the presynaptic membrane into the presynaptic terminal (“reuptake”), where it is either destroyed by monoamine oxidase (MAO) or reenters the granules.

Serotonin is formed from the essential amino acid tryptophan, which is converted under the influence of tryptophan hydroxylase into 5-hydroxytryptophan, which, in turn, is converted into serotonin by decarboxylation. The mediator function of serotonin is carried out in the same way as norepinephrine, and MAO is involved in the inactivation of serotonin at the presynaptic terminal.

Three groups of facts speak in favor of the monoaminergic theory of the pathogenesis of depression.

The first group is pharmacological data. The two main groups of antidepressants - MAO inhibitors and tricyclics - have serotonin and adrenergic effects. The former irreversibly inhibit MAO, thereby preventing the destruction of transmitters in presynaptic terminals, the latter impede reuptake, thereby increasing the residence time of transmitters in the synaptic cleft and thus extending the period of interaction of monoamines with receptors. The following objections are often raised against this evidence:

a) antidepressants do not help in all cases of depression;

b) despite the fact that they act on the same mediator systems, their spectra therapeutic effect quite different;

c) antidepressants appear that do not directly affect monoaminergic structures, for example iprindole;

d) drugs such as amphetamines have a pronounced central adrenopositive effect, but are not antidepressants.

The first of the objections seems unconvincing, since the average effectiveness of antidepressants (50-75%) is sufficient to confirm their inherent antidepressant effect, and the remaining cases of unsuccessful therapy are satisfactorily explained by various circumstances that are not directly related to the mechanism of action of these drugs: their too rapid destruction in body, insufficient strength of the therapeutic effect for a given patient, clinical features of depression, in particular the addition of depersonalization, which causes resistance to antidepressant therapy, etc.

Differences in the therapeutic effects of individual antidepressants are partly due to the fact that the drugs varying degrees affect serotonin and adrenergic processes. In addition, they have other properties: tricyclic antidepressants have an anticholinergic effect, MAOIs also affect GABAergic structures, etc. The antidepressant properties of drugs that do not directly affect monoaminergic processes can be explained by two reasons: firstly, monoamine deficiency is probably an important, but not the only signal in the pathogenesis of depression; secondly, as can be seen from the example of benzodnazepines, some influence on the activity of the turnover of norepinephrine and serotonin under stress can be carried out by them indirectly, through the activation of GABAergic processes. Finally, the lack of antidepressive effect of amphetamine (phenamine) is apparently due to an isolated effect on adrenergic, but not serotonergic processes. Another confirmation of the monoamine hypothesis is the depressogenic effect of reserpine, the pharmacological action of which is based on the depletion of norepinephrine, serotonin and dopamine in nerve endings. The fact that “reserpine depression” occurs in predisposed people (approximately 6% according to F. K. Goodwin, W. E. Bunney, 1971) does not contradict the hypothesis, but only confirms that monoamine deficiency is important, but not the only one a link in the pathogenesis of endogenous depression.

The second group of evidence is based on determining the level of biogenic amines and their metabolic products in patients with depression. Since their direct intravital determination in the brain of a sick person is impossible, the concentration and intensity of metabolism of serotonin and norepinephrine is judged by the content of these monoamines and the products of their metabolism in urine, blood and cerebrospinal fluid.

As is known, the main product of serotonin metabolism in the central nervous system to the periphery is 5-hydroxypidol-acetic acid (5-OHAA), and norepinephrine - vapillylmandelic acid (VMA) and 3-motoxy-4-hydroxy-phepylethyl glycol (MOPG). Early studies of monoamines and their metabolites in patients with depression seemed very controversial, since the majority of these substances found in body fluids are of peripheral origin. However, it was later shown that the ICH is entirely a product of the conversion of peripheral norepinephrine, while a significant part of MOPG is formed from norepinephrine in brain tissue (Ebert M., Kopin I., 1975).

A number of studies have shown that the content of MOPG in the urine of patients with depression is reduced, but in the future a similar decrease could not be found in some patients with endogenous depression. Based on this, attempts were made to identify individual types of depression based on the amount of MOPG excretion (Luchins D., 1970). However, it should be taken into account that, firstly, not all MOPG in urine is of central origin and in some patients its content may increase under stress or due to increased motor activity due to increased noradrenergic processes in the periphery. Secondly, such studies usually do not take into account ethane and the depressive phase syndrome, which, as will be shown below, obviously can significantly affect the metabolism of catecholamines. In addition, given the large individual differences between individuals and the small size of groups, reliable data in studies of this kind can only be obtained when the patient himself serves as his own control, i.e. when the difference in indicators obtained from the same patient during the period of depression and in intermission is processed. Thus, data on a decrease in the level of norepinephrine in the brain during depression, obtained based on the determination of MOPG in urine, are not convincing enough, although similar changes were found in a significant proportion of patients.

As mentioned above, unchanged biogenic amines, VMC and most of the 5-OHIAA, determined in mode and crop, are of peripheral origin and do not allow us to judge the metabolism of norepinephrine and serotonin in the central nervous system. Therefore, their research on cerebrospinal fluid is of particular interest. The article by F. Goodwin, W. Potter (1978) provides summary data from four studies on the content of MOPG in the CSF of patients with depression: in two of them a decrease in MOPG was noted compared to the control, in the other two no difference was found.

Of 6 studies by different authors, only 3 noted a decrease in the content of VMC in the cerebrospinal fluid of depressed patients. The data regarding 5-OHIAA are equally heterogeneous: out of 10 studies, only 5 noted a reduced content of this metabolic product of serotonin in the cerebrospinal fluid compared to the control .

Since the products of monoamine metabolism are very quickly removed from the cerebrospinal fluid into the blood, it can be assumed that their concentration is determined not only by the rate of entry from brain tissue, but also by the rate of removal from the cerebrospinal fluid. Taking this into account, probeneside has recently been used for such studies, which inhibits the transport system that removes VMK and 5-OIAA (but not MOPG) into the blood, and leads to their accumulation in the cerebrospinal fluid. The same article provides data from 5 studies performed with probeneside: in 4 of them, the accumulation of VMK and 5-OIAA was significantly lower than in the control, and only in one - the same (but this last work included only 11 observations).

Thus, more than half of the studies provided data suggesting that patients with depression have a decrease in the levels of norepinephrine and serotonin in the brain. Attempts have also been made to directly determine the level of biogenic amines in the brains of suddenly deceased patients with depression. These studies include only isolated observations and are inconclusive. However, they showed a decrease in serotonin content in certain areas of the brain (Luchins D., 1976).

The third group of facts. If the deficiency of norepinephrine and serotonin in the brain is indeed an essential link in the pathogenesis of depression, then these substances should have an antidepressant effect. However, biogenic amines do not penetrate the blood-brain barrier, so their predecessors, L-DOPA and L-tryptophan, which penetrate the brain and are converted there into catecholamines and serotonin, were used to treat patients with depression. Data on the antidepressant effect of DOPA are overwhelmingly negative, although in some cases a decrease in psychomotor retardation or a transition to mania was noted (Bunney W., 1970).

The antidepressant effect of tryptophan was not noted in all studies (Carrol V., 1971), but a significant part of the researchers were able to establish it, especially in those cases where tryptophan was used in combination with MAOIs (Mikhalenko I.N., 1973).

Our observations correspond to these literature data: the therapeutic effect of tryptophan, used in its pure form, was detected in mild depression. Even a small percentage of indisputably established cases of a positive therapeutic effect (i.e., in the reliable absence of the likelihood of spontaneous remission or any other therapeutic effect) indicates that the drug, in this case tryptophan, to a certain extent has a specific antidepressant effect, namely This is the fundamental issue.

Tryptophan does not help in all cases of depression, but practically no treatment method, including ECT, gives 100% positive results, and a number of factors can interfere with the implementation of the effect of tryptophan: not all tryptophan enters the central nervous system for the synthesis of serotonin: some is converted into serotonin at periphery, some go to the kynurenine metabolic pathway, and it is possible that some metabolic products formed along this pathway may interfere with the antidepressant effect (Lapin IP, Gura S, 1973). It should also be taken into account that side effects prevent an increase in the dose of tryptophan, and in addition, its increase activates the enzyme tryptophan pyrrolase, which directs tryptophan to the kynurenine pathway (Curzon G., 1969). Slowing down the inactivation of tryptophan and its transformation products up to serotonin, carried out by MAO inhibitors, sharply enhances the therapeutic effect of tryptophan and the antidepressant itself.

The lack of antidepressant effect of L-DOPA seems more obvious, but this still does not allow us to deny the role of NA deficiency in the pathogenesis of depression. Firstly, side effects DOPA is significantly more potent than tryptophan and is more difficult to increase doses, so the lack of antidepressant effect may be due to insufficient dosage. Secondly, enhancing DOPA affect with MAO inhibitors is risky due to the reaction.

Incompatibilities between these drugs. Thirdly, the bulk of the administered DOPA is converted into dopamine, then norepinephrine and then into adrenaline in the periphery, and there is a reciprocal relationship between adrenaline in the periphery and norepinephrine in the brain (Baru A. Y., 1970), so that the level of adrenaline increases when administered DOPA counteracts the increase in norepinephrine levels in brain tissue.

Thus, none of the three given groups of factors contradicts, and in most cases corresponds to the hypothesis according to which deficiency of norepinephrine and serotonin plays a role in the pathogenesis of depression. The ambiguity of experimental, mainly indirect, data has led to significant differences in their interpretation. At first, the question was raised about which of the mediators - norepinephrine or serotonin - plays a leading role in the pathogenesis of depression. This is how the “catecholamine” and “serotonin” hypotheses of the pathogenesis of depression were created. However, the further accumulation of facts forced us to abandon such a straightforward approach, and most researchers adhere to the unitary hypothesis, according to which in depression there is a deficiency of both NA and serotonin, and each of these monoamines is “responsible” for a certain set of psychopathological symptoms: serotonin for mood, and ON - for motor activity(Lapin I.P., Oksenkrug G.F., 1969). A comparison of the therapeutic effects of tricyclic antidepressants (amitriptyline and imipramine) and their demethylated derivatives (nortriptyline and desipramine) showed that the former have a greater anti-anxiety component of action and at the same time prevent the reuptake of serotonin, while demethylated derivatives affect predominantly the reuptake of serotonin. norepinephrine uptake, i.e. have a more pure norepinephrine-positive effect.

Based on this, we can conclude that serotonin deficiency is associated with anxiety.

From the same clinical, pharmacological and biochemical data, hypotheses are constructed according to which there are clinically similar, but biochemically different forms of depression - serotonin-deficient and norepinephrine-deficient. The former are, accordingly, better treated with drugs such as amitriptyline, the latter - with desipramine or nortriptyline (Goodwin F., Potter W., 1978). Obviously, such an approach is still poorly substantiated, and although a number of authors are exploring the possibility of a “biochemical clustering” of depression, further evidence is needed for this.

DISORDERS SECRETION OF GLUCOCORTICOIDS

A number of studies have noted an increase in the level of glucocorticoids in patients with endogenous depression (Gibbons J., Mc Hugh, 1962, etc.). As is known, the secretion of glucocorticoids is carried out under the influence of ACTH secreted by the posterior lobe of the pituitary gland; in turn, ACTH secretion is stimulated by corticotropin releasing factor (CRF) produced in the hypothalamus. Regulation of glucocorticoid secretion is carried out according to the principle of negative feedback: an excess of the hormone in the blood leads to inhibition of CRF secretion, which entails a decrease in ACTH levels and, accordingly, a decrease in glucocorticoid secretion. An excessive decrease in the level of glucocorticoids in the blood activates the release of CRF. Thus, in normal conditions the corticosteroid content is automatically maintained at a stable level.

Stress stimulates the release of corticosteroids. Normally, there are distinct circadian fluctuations in the secretion of glucocorticoids: in humans and diurnal mammals, their maximum level is observed in the second half of the night and the first morning hours, the minimum level is in the late evening and early night.

The dexamethasone test (DT) is used to identify dysregulation of adrenal function. Normally, the administration of the synthetic glucocorticoid dexamethasone through a negative feedback mechanism leads to a decrease in the secretion of glucocorticoids by the adrenal glands. In cases where regulation is impaired (for example, in Itsenko-Cushing's disease), dexamethasone loading does not cause a decrease in the secretion of ACHT and adrenal hormones. A similar decrease in the body’s sensitivity to the inhibitory effect of dexamethasone was also noted in patients with endogenous depression (Carrol B., Curtis G., Mendels J., 1976, etc.), although not all studies were able to confirm this fact. One of the possible reasons for these discrepancies is the dose of dexamethasone (2 mg), designed to detect such severe disorders as Cushing's disease, in which the secretion of glucocorticoids is impaired to a much greater extent than in depression. An increase in the sensitivity of the dexamethasone test was achieved by lengthening the interval between giving dexamethasone and determining the level of glucocorticoids, and DT disturbances were found in a significant proportion of patients with endogenous depression (Carrol B., Curtis, G., Mendels J., 1976).

Taking into account these data, as well as the connection between the secretion of releasing factors and the content of biogenic amines in the hypothalamus (Frohman L., Stachura M., 1975), we, together with M. N. Ostroumova, studied the reaction to dexamethasone in patients with various forms of depression. To increase the sensitivity of DT, its modification was used, proposed by M. N. Ostroumova (Ostrumova M. P., Tsyrkina E. V., 1978), in which the dose of dexamethasone was 0.5 mg. The study aimed to:

To identify the frequency and degree of DT disorders in patients with various forms depression: endogenous, reactive, as well as within the framework of schizophrenia, involutional and organic psychoses;

To compare DT in the same patients during the period of depression and intermission;

To try to establish a relationship between DT indicators and the level of biogenic amines in patients with depression and in the control group.

To do this, we studied the influence of the precursors of norepinephrine and serotonin - DOPA and tryptophan, as well as some psychotropic drugs on DT indicators.

The dexamethasone test was performed in the first days after admission to the hospital (usually on days 2-4) before starting therapy. If the patient received before hospitalization psychotropic medications, then the break before the study was at least 7-10 days. At 9:00 am on the first day of the study, blood was taken from a vein from the patient on an empty stomach. At 23:00 the same day, 0.5 mg of dexamethasone was given, and at 9:00 the next day a repeat blood sample was taken. 11-Oxycorticosteroids (11-OX) were determined in blood serum using the fluorometric method. The percentage of suppression of 11-OX secretion after dexamethasone loading was calculated, and if it was less than 30%, then the test was considered pathological.

DT was carried out in 52 patients with endogenous depression - 15 men and 37 women aged from 18 to 65 years. In 29 of these patients, DT was carried out over time during the period of depression and in remission. In addition, we studied 8 patients with reactive depression hospitalized for suicide attempts, 9 patients with depressive-paranoid syndrome within the framework of schizophrenia and involutional psychosis, and in these patients delusions, hallucinations and Kandinsky-Clerambault syndrome were combined with distinct depression, characterized by daily mood swings and vital longing. The control group included 85 healthy people- 22 men and 63 women aged from 20 to 65 years and 11 psychotic patients, mainly with schizophrenia, without depression. The DT results are presented in table. 6. As can be seen from the table, the average indicators in patients with endogenous depression were statistically significantly different from the controls, and resistance to dexamethasone (pathological DT - suppression less than 30%) was found in 36 patients out of 52, i.e. in 69%, while in the control group pathological DT was detected in 8 out of 85 people, i.e. in 9%. These differences are also statistically significant. When studying DT over time, it was found that in all patients during the period of remission, normalization of indicators occurred, as can be seen from Table. 7.

TABLE No. 6

Results of the dexamethasone test in patients with depression and in control groups
	Number of observations	Level 11-OX mcg/l
		Original	After dexamethasone
Healthy
Endogenous depression				19±5 (p<0,001)
Reactive depression
Depressive syndrome in patients with schizophrenia				14±10 (p< 0,001)
Psychotic patients without depression

TABLE No. 7

Results of the dexamethasone test in patients with MDP over time
Depression			Remission
11-OX µg/l			11-OX µg/l
Original	After dexamethasone		Original	After dexamethasone

Thus, the data presented clearly show that dysregulation of corticosteroid secretion (pathological DT) is associated with an attack of endogenous depression: test scores during the depression period were significantly different from the control, and after the cessation of the phase they completely returned to normal. During depression, not only was sensitivity to the inhibitory effects of dexamethasone reduced, but baseline 11-OX levels were also elevated. The fact that the indicators obtained in MDP patients in remission are completely identical to the indicators of healthy controls indicates that the disorders found in depression are inherent specifically in the state of depression, and not in MDP itself at different stages of this disease (i.e., not only in depression, but also in mania and intermission). Considering this, DT can obviously be used as an auxiliary method for recognizing depression.

The fact that DT turned out to be pathological only in 2/3 of patients with endogenous depression probably depends on a number of factors: firstly, the very method of assessing the effect of dexamethasone by 11-OX in the blood carries a certain probability of error: the secretion of corticosteroids by the adrenal glands is not carried out evenly, but in short peaks lasting several minutes, with subsequent intervals. Therefore, although blood is taken 2 days in a row at the same time, it is possible that on one day the blood will be taken at the height of the peak, and on the other day at the decline. This circumstance creates the possibility of distortion of test data in each individual case, although when assessing the average results of the group, these fluctuations, the direction of which is random, should be leveled out. The second reason may be that the grouping of patients is not clear enough. The results of the use of dibenzodiazepines (see Chapters 4 and 6) showed that in some patients with clearly expressed depressive symptoms within the framework of an anxious-depressive state, the leading component of the syndrome was anxiety, and the depressive symptoms themselves could be considered secondary. And although these patients were diagnosed with endogenous (usually involutional) depression, the DT indicators could be unimpaired. Thirdly, although in some patients the suppression of 11-OCS was regarded as normal (30-40%), during the period of remission it increased to 60-80%. This indicates that the 30% criterion as an indicator of pathological DT is arbitrary.

Given these observations, it can be argued that changes in the sensitivity of the systems that regulate the secretion of corticosteroids are a fairly reliable sign of endogenous depression.

Patients with depressive-paranoid syndrome within other nosological forms responded to dexamethasone loading in exactly the same way as patients with endogenous depression (see Table 6). As mentioned above, although the symptoms of these patients included such heterogeneous manifestations for MDP as the ford of persecution and relationships, hallucinations, pseudohallucinations, phenomena of mental automatism, etc., the depressive symptoms themselves were quite pronounced in them and reached the level of vital melancholy. Thus, pathological DT indicates the presence of depression at a psychotic level, which arose within the framework of both purely affective psychosis and other psychoses in combination with the symptoms inherent in these psychoses. In other words, in these cases the biochemical mechanisms of depressive states are identical. This assumption is confirmed by the fact that DT indicators in patients with schizophrenia without severe depression were normal.

Normal DT levels were found in 7 out of 8 patients with reactive depression. All these patients were hospitalized after suicide attempts caused by a rather severe psychotraumatic situation. Their symptoms included anxiety and low mood. The main content of their experiences were events associated with psychotrauma. As a result of treatment with tranquilizers, their mental state usually returned to normal within a few days, less often within 1-2 weeks. It is interesting to compare these observations with three cases of reactively provoked endogenous depression. At first, they did not differ significantly from patients with reactive depression: they were also hospitalized after suicide attempts caused by psychotrauma, but their DT results were pathological, and subsequently, over the course of 1.5 years of observation, repeated depressions occurred in these patients, and in 1 manic phase.

Thus, all the data presented indicate that in depression (endogenous and psychotic) there is a decrease in sensitivity to the inhibitory effect of dexamethasone.

The absence or weak suppression of 11-OX levels by dexamethasone indicates a violation of the feedback mechanism in the regulation of glucocorticoid secretion. It can be assumed that the cause of this disorder, at least in depression, is a deficiency of biogenic amines in the brain that control the secretion of releasing factors in the hypothalamus, including corticotropin releasing factor. In order to establish the role of serotonin and norepinephrine in the regulation of glucocorticoid secretion in a group of patients, DT was carried out against the background of therapy with tryptophan and DOPA.

20 people received L-tryptophan: 8 patients with endogenous depression, 3 mentally ill without depression and 5 subjects without psychosis, including 4 elderly people over 65 years old. L-DOPA was taken by both people - 1 with endogenous depression, 2 with psychopathy, 6 with Parkinson's disease and 2 healthy subjects.

DT was carried out before the start of therapy, and then during its process at maximum doses of the drug. L-tryptophan was prescribed in doses of 3.5 to 7 g per day, with doses occurring in the second half of the day so that the bulk of the drug enters the body during a period of less tryptophan pyrrolase activity. The duration of the course ranged from 7 to 14 days. The second definition of DT usually occurred on the penultimate and last days of treatment. The results are presented in table. 8.

In animal experiments, it was shown that an increase in NA content in the brain reduces the secretion of cortisol, and its deficiency accordingly increases the secretion of glucocorticoids (Scapagnini U. and Preziosi P., 1973). This is confirmed by experiments with direct application of norepinephrine to the hypothalamus: norepinephrine inhibited the production of CRF (Buckingham J., Hodges J, 1977).

As can be seen in the table. 8, the norepinephrine precursor DOPA caused a slight decrease in the initial level of 11-OX and at the same time slightly increased the sensitivity of feedback mechanisms to the inhibitory effect of dexamethasone.

Data on the effect of serotonin on the regulation of adrenal function are extremely contradictory: on the one hand, there are observations that its predecessor, tryptophan, increases the secretion of glucocorticoids (Vernicos-Danellis I., Berger P., Barchas J., 1973); on the other hand, it has been shown that under the influence of serotonin, the secretion of ACHT and cortisol decreases, and with its deficiency, it increases (Vermes I., Molnar D., Telegdy C, 1972). In studies by J. Buckingham and J. Hodges (1977), it was clearly shown that the application of serotonin to the hypothalamus leads to an increase in the production of CRF.

TABLE No. 8

Results of the dexamethasone test during treatmentL-DOPA,L-tryptophan, seduxen and phenazepam
	Number of observations	Level 11-OX mcg/l before treatment
		Original	After dexamethasone
L-tryptophan
Seduxen
Phenazepam

CONTINUATION

	Number of observations	Level 11-OX mcg/l after treatment
		Original	After dexamethasone
L-tryptophan
Seduxen
Phenazepam

* The differences are statistically significant.

The data given in table. 8, allow us to explain this contradiction: under the influence of tryptophan, the suppression of 11-OX secretion by dexamethasone statistically significantly increased, which indicates an increase in the sensitivity of negative feedback mechanisms. With an increase in the sensitivity of inhibitory mechanisms, one would expect a slight decrease in the initial level of 11-OX, but treatment with tryptophan did not lead to its changes. On the other hand, there was no increase in the level of 11-OX, although, based on the data of J. Buckingham and J. Hodges (1977), this should have been expected.

Our data become understandable if we assume that serotonin has a dual effect on the secretion of glucocorticoids: on the one hand, it stimulates the secretion of CRF, directly \ acting on the hypothalamus, on the other hand, it increases sensitivity to the inhibitory effect of corticosteroids, probably due to its effect on extrahypothalamic structures. If this assumption is correct, then when serotonin levels in the brain are high, the increase in cortisol levels (during circadian increases or stress) will be large, but quickly damped. On the contrary, with a lack of serotonin, the magnitude of the rises will be smaller, but the normalization of the level provided by negative feedback will be slowed down or completely disrupted, as a result of which diurnal fluctuations in cortisol levels should be smoothed out, mainly due to the evening hours, when it should normally be low. Available experimental data confirm this: the drug parachlorophenylalanine, which has an antiserotonin effect, smoothes the stress response and circadian fluctuations by increasing basal levels of corticosteroids. In endogenous depression, which is characterized by serotonin deficiency, sharp disturbances in the circadian rhythm of cortisol secretion have also been found (Disrupted 24-hour Patterns ..., 1973). Indirect confirmation that the impaired regulation of glucocorticoid secretion in depression is associated with monoaminergic processes is the results of the use of tranquilizers - benzodiazepine derivatives: seduxen (diazepam) and phenazepam - in patients with anxiety-depressive syndrome. 6 women were treated with Seduxen in doses of 30 mg per day, and 27 women with MDP (late-onset monopolar course) and involutional psychosis were treated with phenazepam (2-6 mg per day). DT was carried out before the start and on the 7-10th day of therapy.

As is known, tranquilizers of this group reduce the turnover of norepinephrine and serotonin in the brain, i.e. reduce the rate of their destruction and synthesis (Dominic J., Sinha A., Barchas S., 1975). This effect likely prevents the depletion of these monoamines in the brain and reduces their deficiency. From the table Figure 8 shows that the effect of tranquilizers leads not only to a decrease in the initial level of 11-OX , what could be expected, given the anti-anxiety (anti-stress) effect of these drugs (Valdman A.V., Kozlovskaya M.M., Medvedev O.S., 1979), but at the same time the suppressive effect of dexamethasone significantly increases. Since during anxiety (stress) norepinephrine is depleted faster, since its resynthesis is slower than serotonin, the decrease in the initial level of 11-OX under the influence of tranquilizers can be explained by the accumulation of norepinephrine, while the accumulation of serotonin obviously leads to increased sensitivity regulatory feedback mechanisms, i.e. to an increase in the percentage of 11-OX suppression by dexamethasone.

Based on the above literature and our own data, we can formulate some assumptions about the role of disorders of the hypothalamic regulation of corticosteroid secretion and deficiency of biogenic amines in the pathogenesis of depression. As mentioned above, available evidence indicates that in endogenous depression there is a deficiency of norepinephrine and serotonin in the brain, and the deficiency of each of these mediators is associated with certain manifestations of endogenous depression. In addition, norepinephrine and serotonin are involved in the regulation of corticosteroid secretion: a deficiency of norepinephrine leads to an increase in the level of corticosteroids, and a deficiency of serotonin leads to a decrease, and at the same time to dysregulation through a negative feedback mechanism. A deficiency of both monoamines should lead to such a violation of the secretion of glucocorticoids when, with a relatively high level in the morning, there is no normal decrease in their concentration in the evening and night hours. Thus, conditions are created under which increased secretion of corticosteroids occurs, and this increase extends throughout the entire daily period, as a result of which various enzyme systems are under the continuous influence of glucocorticoids. In other words, this chronic hypercortisolism characteristic of depression can be thought of as a model of chronic stress.

It is known that stress and hypercortisolism lead to depletion of the brain in biogenic amines (Bliss E., Zwanziger J., 1966). The specific mechanisms by which hypercortisolism leads to a decrease in norepinephrine and serotonin levels have only been partially identified. Thus, there is evidence of activation by corticosteroids of the enzyme tryptophan pyrrolase contained in the liver, which ensures the transfer of tryptophan to the non-purine metabolic pathway, reducing the amount of tryptophan entering the brain and used for the synthesis of serotonin (Curzon G., 1969). Corticosteroids (hence stress) increase the activity of liver tyrosine transaminases, which leads to a decrease in tyrosine levels in the blood (Nemeth S., 1978). This, in turn, helps to reduce the synthesis of catecholamines in the brain.

Thus, with depression, a kind of vicious circle is created: a deficiency of norepinephrine and serotonin in the brain causes increased secretion of shockocorticoids, and hypercortisolism, in turn, leads to a deficiency of these monoamines. This hypothesis connects numerous data on monoamine deficiency, on the one hand, and on increased levels of glucocorticoids, as well as disruption of the circadian rhythm of their secretion during endogenous depression, on the other. Obviously, the emergence of such a vicious circle can be caused by defects and disturbances in various links of the pathogenetic chain, which explains the polyetiological nature of MDP. Thus, genetically determined inferiority of individual enzymes involved in the synthesis and destruction of serotonin and norepinephrine can lead, especially in the presence of additional load, to a deficiency of these monoamines. This additional load may include stress, which leads to increased breakdown and synthesis of monoamines in the brain, and the effect of drugs such as reserpine, which also cause accelerated breakdown of serotonin and norepinephrine. Indeed, it is well known that acute stressful situations provoke (“precipitate”) attacks of depression, and reserpine causes depression in a significant proportion of predisposed patients. In these cases, the pathological process is “started” in the “monoamine link” of pathogenesis. In other cases, the primary ringing is the “stress-corticosteroid” link. Thus, it is known that persons with. Cushing's syndrome of various origins often suffer from depressive conditions. Very often, the appearance of depression is associated with treatment with corticosteroid drugs for a long time.

As was shown in Chap. I, chronic stress significantly increases the likelihood of endogenous depression. All these data fit well into the proposed hypothesis of the pathogenesis of depression. But no matter what link an initial breakdown or “breakdown” has occurred; the pathogenesis of depression is based on a violation of the relationship between these links, and the disease process unfolds only when both links - “monoamine deficiency” and “impaired corticosteroid secretion” - form a vicious circle system (positive feedback).

“The information underlying Iissiidiology is designed to radically change your entire current vision of the world, which, together with everything that is in it - from minerals, plants, animals and humans to distant Stars and Galaxies - is in reality unimaginably complex and an extremely dynamic Illusion, no more real than your dream today."

Content:

Introduction.

Chapter 1. A scientific view of depression.

1.1. Concept and etiology of depression.

1.2. Classification and main symptoms of depression.

1.3. Biological hypotheses (mechanisms) for the development of depression from a scientific perspective.

Chapter 2. A look at depression from the perspective of issiidiology.

2.1. Causes of depression.

2.2. Neurobiological changes during depression.

2.3. The positive impact of depression from the perspective of science and issiidiology.

Chapter 3. Methods for getting out of depression.

Conclusion.

​ Literature.

Introduction

Currently, the relevance of the problem of affective disorders and, first of all, depression is determined by its great medical and social significance. This is due to the high prevalence of depression among the population, the annual increase in incidence, difficulties in diagnosis, and insufficiently clearly developed approaches to its prevention and treatment.

Depression has been known to humanity for as long as it has been aware of itself, but recently it has become more noticeable not only according to health statistics, but also in the entire way of life. Modern human living conditions increasingly create the problem of prolonged mental and physical stress. If a hundred years ago the share of depression in the structure of mental disorders was several percent, now it is an order of magnitude higher (up to 15% of the total population of the planet, and in developed countries - up to 20%). According to the WHO forecast, by 2020, in terms of prevalence, depression may take first place in the world among all diseases. According to D. Blazer, major depressive disorder affects about 6% of men and 18% of women, and the risk of its occurrence, according to J. Kay, throughout life is 7-12% for men and 20-25% for women. In somatic patients, the prevalence of depression reaches 22-33%, and among some categories of patients (oncology, with myocardial infarction) it develops in 45% of cases. In the presence of a depressive disorder, the length of hospital treatment for various diseases increases, and their prognosis also worsens. At the same time, people with this pathology experience a significant limitation in their temporary ability to work, and high rates of disability are observed. This disease brings suffering to both the patient and his loved ones.

Unfortunately, people are very little aware of the typical symptoms and consequences of depression., therefore, many patients receive help when the condition becomes protracted and severe, and sometimes it is not provided at all. It is often perceived both by the wearer and by others as a manifestation of bad character, laziness and selfishness, promiscuity or natural pessimism. 80% of patients with depression initially seek help from general practitioners, and the correct diagnosis is made in approximately 5% of them. Even fewer patients receive adequate therapy. Thoughts about a serious, unrecognized somatic illness appear, which, through a vicious circle mechanism, leads to worsening depression. The method of treatment, in general its very possibility, depends both on the nature of the disease and on many other factors.

CHAPTER 1. A scientific view of depression

1.1. Concept and etiology of depression

The duality of depression lies in the fact that, on the one hand, it is a special state of the psyche, and on the other, it is a somatic morbidity. This makes it the subject of study of both psychology and medicine, but the leading role in the study of this pathology, along with clinical medicine, still belongs to psychology.

In psychology, depression is dealt with by the theory of emotions (in particular, the section devoted to affects) and pathopsychology - a section of medical psychology that studies the patterns of disintegration of mental activity and personality traits during illness.

These sciences go hand in hand here, constantly supporting each other. In the clinical picture of different variants and different stages of the course of depression, various somatic disorders are almost invariably, and sometimes almost exclusively, present - from subtle vegetative, metabolic-endocrine changes, shifts in the daily rhythm of activity up to trophic disorders. These include dysfunction of the adrenal glands, thyroid and parathyroid glands, pernicious anemia, viral infections, cancer, epilepsy, vitamin deficiency, hysterectomy, rheumatoid arthritis and others. On the other hand, some somatic diseases often act as a provoking factor for depression. According to research, they rank fifth among the most common causes of depression (Leff, Roatch, Bunney, 1970; Paykel, Klerman, Prusoff, 1970). This suggests the conclusion that depression is both a somatic and somatoneurological pathology.

Depression(from the Latin word depressio - suppression) is a psychological disorder that is characterized by low mood (hypotymia), inhibition of intellectual and motor activity, sometimes psychomotor agitation, painful emotions and experiences, a sense of guilt for past events and a feeling of helplessness in the face of life's difficulties, combined with a feeling of hopelessness, decreased vital impulses, and somatoneurological disorders. Depression is characterized by cognitive impairments such as a negative, destructive assessment of one’s own personality, the outside world and the future; many people withdraw into themselves and isolate themselves from others. All this contributes to decreased sociability; drives, motives, and volitional activity also sharply decrease. In this case, there is difficulty in thinking, thoughts are confused, flow slowly, it becomes difficult to concentrate on a specific issue, absent-mindedness and forgetfulness appear.

In this state, thoughts and feelings are distorted and do not reflect the actual state of things, the person experiences anxiety and is in the grip of fears. In severe, long-term states of depression, suicide attempts are possible. In any of its “outfits,” depression is a condition characterized by an increased distortion of a person’s perception of himself, other people and the world around him.

To one degree or another, all of us have a risk of developing a depressive disorder. Events that lead to tension and stress occur in every person's life and can serve as a trigger for depressive disorder. The following are available depressogenic factors- somatic (severe and chronic diseases), age-related (childbirth, menopause), environmental (chronic intoxication, various types of radiation and noise), iatrogenic, low social support, lack of significant interpersonal connections, divorce, alcohol or drug addiction, deviations in the content of hormones in the body, a hereditary predisposition in some people.

The onset of the disease, according to doctors, is associated with a disruption in the processes of biochemical activity of the brain. And the general principled position of psychoanalysts is to recognize all depression as an exogenous disorder that arose in response to a traumatic event. Although depression can be considered as an autonomous formation, that is, arising once as a result of a stressful (frustrating) influence and persistent (persistent) throughout life, etiologically it is defined as reactive.

According to A. Beck (American psychiatrist, president of the Institute of Cognitive Therapy and Cognitive Research), depressive symptoms are the result of a kind of false “unconscious conclusions”, and all manifestations of the depressive syndrome are a consequence of the activation of negative cognitive patterns (model, sample). The cognitive theory of depression (A. Beck 1967, 1976, A. Bandura 1977, 1983) is based on the assertion that a person’s non-optimistic view of himself, the world and his future is the main determinant (decisive, determining factor) of depression. A. Beck explains most typical depressive symptoms, such as paralysis of the will, suicide attempts and self-depreciation, as the result of specific cognitive (exploratory, cognitive) determinants. However, some authors consider the reduction of the depressive symptom complex to cognitive causes unproven, and cognitive impairment is more likely a consequence rather than a cause of depressive states.

According to British scientists, main cause of depression is a gene that is responsible for the normal functioning of the brain. In those who suffer from depression, a gene called MKP-1 is twice as active as in those whose mental health is not a concern. This gene is responsible for the functioning of neurons, which are used to transmit and process information and also transmit electrical and chemical signals.

So, depressive disorders are distinguished that have an internal biological cause - endogenous depression, and an external one (in the broad sense as an exogenous effect) - reactive depression. Factors that cause endogenous depression and factors that provoke reactive depression belong to two fundamentally different classes of causes. The first include genetic, biochemical processes occurring in the internal environment of the body; the second - social, psychological processes that determine personality adaptation.

1.2. Classification and main symptoms of depression

There is no uniform classification of depressive disorders. Attempts to organize the accumulated data on depressive disorders have been implemented in numerous typologies and classifications (Kleist 1928, Ploticher 1968, Nadzharov 1968, Yu.L. Nuller 1973, Kielholz 1970, Khvilivitsky 1972 and others). A number of taxonomies are built according to the etiopathogenetic principle (endogenous, reactive, symptomatic depression), a number - according to the phenomenological principle (taking into account the criteria of severity and structure of the syndrome).

From a general pathological point of view, the classification of depressive manifestations is as follows:

1. By etiology (with a fundamental division into: exogenous - due to mental and other external trauma and endogenous - due to intracerebral intermediator cerebral disorders and constitutional anomalies). In this case, there is always the influence of a complex of etiological factors, both endogenous and exogenous, with the leading role of any one.

2. Along the flow (unipolar and bipolar - with fluctuations in affect from reduced to painfully elevated).

3. By pathogenesis (primary and secondary - against the background of concomitant mental and somatic disorders, the action of unfavorable external factors, side effects of treatment).

4. According to clinical and psychopathological characteristics(non-psychotic and psychotic - with symptoms of a gross violation of the reflection of reality and oneself in it).

5. According to the complexity of the syndrome(typical - simple, atypical - with additional symptoms or reduced).

6. Along the course (transient and recurrent).

7. By duration (short-term, long-term, chronic).

8. According to the pathomorphological picture(inorganic and organic).

Unipolar depression(major or clinical depression) is the most common form of depressive disorder. The word monopolar means the presence of one extreme position - a “pole” - in the range of emotions, which is characterized accordingly by only one - sad, depressed - mood. As a rule, this is a persistent feeling of sadness or complete joylessness, insomnia, inability to concentrate, forgetfulness, loss of appetite, pain in different places, and a heavy feeling of deep mental pain - melancholy. In this state, a person considers himself worthless, incapable of anything, and his situation is hopeless. Self-esteem drops. In most patients, an attack of depression, regardless of the cause of the disease, goes away on its own within 6-9 months.

Major depression has several more common forms. This psychotic depression(in addition to the symptoms of depression itself, delusions and hallucinations develop, the threat of suicide increases sharply, the patient must be hospitalized immediately), atypical depression(there is a mixed picture of symptoms typical of major depression and atypical), postpartum depression, postpartum psychosis. Atypical depression is a form of depressive disorder in which, along with the typical symptoms of depression, specific signs such as increased appetite, weight gain, increased drowsiness and so-called “emotional reactivity” are noted. Premenstrual dysphoric disorder (from the Greek dysphoréo - hard to bear, irritated) disorder is a cyclically recurring mood disorder that affects 3-5 percent of women who retain the ability to menstruate. Women suffering from true premenstrual dysphoric syndrome experience anger, irritability, anxiety, fatigue, sadness, cravings for unusual foods, guilt and self-blame, and tearfulness on a monthly basis, usually during the week before their period begins.

Dysthymiaor, as it is also called,minor depression- this is a long-term form of depressive disorder, which is characterized by a persistent feeling of joylessness, lack of a sense of humor, and it is difficult to smile even for a joke. Often in a state of dysthymia, people say about themselves that they have been sad “since birth.” Anxiety predominates in thoughts; any events and circumstances in life are perceived only as failures. Thoughts of suicide may come to mind, although these are not specific plans to take one’s own life, as with major depression. This condition persists constantly or improves and goes away for a short time. Symptoms are not as severe as those of clinical depression, although people with dysthymia are also susceptible to recurrent episodes of clinical depression.

Seasonal affective disorderis a form of depression that occurs strictly at certain times of the year. Most people suffering from this disease feel depressed and lethargic in winter, while in summer their mood is normal and even joyful. The causes of seasonal affective disorder are still unclear. They indicate, in particular, a reduced level of the hormone serotonin, fluctuations in the content of the hormone melatonin, and a violation of the body’s daily biorhythms.

Bipolar depression(also known as manic depression or manic-depressive psychosis). In bipolar depression, a person's mood shifts between extreme positions or poles: between a sad mood (depression) and a joyful mood (mania). In the middle of the 19th century in France, J.-P. Falret and J. Baillarger independently described alternating states of depression, characterized by alternating phase changes (manic and depressive). J.-P. Falret defined it as “circular madness” (folie circulaire), and J. Baillarger as a form of “double madness” (folie a double forme). Depending on the phase of the attack, a person experiences various painful experiences. During the depressive phase of the disorder, the same symptoms appear as in major depression. As the mood changes, a state of mild mania (hypomania) may occur, which is characterized by an abnormally elevated mood, pronounced excessive sociability, emotional liveliness, and an unprecedented surge of strength. As mania increases, irritability appears, a feeling of extreme joy gives way to anger, excitement becomes increasingly unbridled, and actions become unpredictable. Any failure is simply unbearable, attacks of anger when someone tries to restrain and besiege, and there are also excessively high demands on others. Such mood changes usually have little or no connection with everyday events, so the manifestations of the disease can significantly disrupt the normal course of life and the performance of daily tasks.

Bipolar depression attacks can occur and develop in different ways. Bipolar depression, like major depression, can also be dangerous. During the depressive phase, the patient is overcome by thoughts of suicide; during the manic phase, his sobriety and rational abilities disappear, and he is unable to foresee the serious consequences of his actions.

1.3. Biological hypotheses (mechanisms) for the development of depression from a scientific perspective

Research in recent years has expanded the understanding of the pathogenesis of depression, introducing the concept neurobiological mechanisms of development of depressive disorders. To date, the following neurobiological abnormalities associated with the development of depressive disorder are known: an imbalance in the activity of the serotonin, noradrenergic and dopaminergic systems of the brain; neurohormonal disorders concerning, first of all. functions of the hypothalamic-pituitary-adrenal system; structural and functional disorders in the limbic system of the brain, a decrease in the volume of the hippocampus, a decrease in the functional state of the frontal areas of the cortex of the left hemisphere and activation of the frontal and temporal areas of the cortex of the right hemisphere, disruption of circadian rhythms.

The central role is played by disorders of various parts of the hypothalamic-pituitary-adrenal axis (HPA axis), which are accompanied by hypercortisolemia, enlarged adrenal glands, changes in the circadian rhythm, and a decrease in the number of cortisol receptors in the hippocampus. Pathological circadian fluctuations in cortisol levels in the blood are observed, especially a prolonged increase in cortisol levels at night, when in healthy people it is practically absent. Using modern diagnostic methods, for example, the corticoliberin-dexamethasone test, HPA axis disorders were detected in 80% of patients with depression.

Long-term hypersecretion of cortisol causes various metabolic disorders: decrease in muscle mass, resistance (resistance, resistance) of cells to the action of insulin, hyperglycemia, decreased immunity, and so on. In addition, high cortisol levels have neurotoxic effects. It has now been found that a decrease in neuronal plasticity of the hippocampus in depression and such manifestations as disturbances in the structure and function of dendrites (shortening, decreased synaptic contacts), death of nerve and glial cells are largely associated with prolonged exposure to high levels of cortisol.

During the second half of the 20th century, the most common theory was that studying endogenous depression. This theory postulates primarily a deficiency of serotonergic and adrenergic neurotransmission in the central nervous system (CNS). The noradrenergic and serotonergic systems are among the main neurotransmitter systems of the brain; they are involved in the formation of feelings, thinking and behavior. Most serotonergic neurons are localized in the raphe nuclei and brainstem. Serotonergic projections to the frontal cortex regulate mood; in the basal ganglia - control motor activity; to the limbic system - responsible for the occurrence of anxiety and panic, to the hypothalamus - involved in appetite control, to the sleep centers of the brain stem - forming slow-wave sleep. The hypothetical pattern of serotonin deficiency according to S.M. Stahl is manifested by depressive mood, anxiety, panic, phobias, obsessive-compulsive disorders, bulimia and sleep disorders. A deficiency of norepinephrine in the form of impaired attention and working memory; slower processing of information processes, psychomotor retardation, increased fatigue. Another indirect evidence of the presence of serotonin deficiency in the brain during depression is data obtained in experiments using a diet low in the amino acid tryptophan, from which serotonin is synthesized in the body. This tryptophan-free diet leads to a rapid decrease in tryptophan levels in the plasma and brain and a sharp slowdown in serotonin synthesis. At the same time, in healthy people, depressive symptoms do not appear, but in patients with depression, a rapid relapse is observed.

It is possible that central dopaminergic deficiency also plays a role in the pathogenesis of depression. Dopamine is the third monoamine after serotonin and norepinephrine. In recent years, researchers have shown increasing interest in dopamine. It has recently been discovered that by activating the dopaminergic system, an antidepressant effect can be achieved.

Against this background, the role of tryptophan was also actively studied, since it, as a precursor of serotonin, is able to influence its content in the brain and in the periphery (blood platelets). At the beginning of the 21st century, the “tryptophan-kynurenine” hypothesis for the development of depression was first formulated, postulating a connection between immune activation and an increase in the rate of tryptophan degradation along the kynurenine pathway, accompanied by neurochemical and cellular disorders in brain tissue.

Tryptophan is an essential amino acid that is metabolized in the brain and in the periphery in two ways: through the methoxyindole pathway, which leads to the formation of serotonin and melatonin, and through the kynurenine pathway. Normally, there is a balance between these two pathways. In this case, the enzyme IDO is activated (under the influence of pro-inflammatory cytokines) and is involved in the metabolism of tryptophan outside the liver in tissues such as the lungs, placenta, kidneys, spleen, blood and brain. This “extrahepatic” metabolism of tryptophan overshadows the metabolism of tryptophan in the liver. In this case, the breakdown of tryptophan along the kynurenine pathway occurs mainly in the central nervous system, in the blood and lymphoid tissues.This leads to a deficiency of serotonin in the brain and a decrease in serotonergic transmission (transition, transmission) in serotonin neurons.

To discuss the pathogenesis of depression, the concept of neuronal plasticity of brain structures has recently been widely used. This hypothesis is based on numerous data from neuroimaging studies indicating structural damage to the brain in depression. This is mainly a decrease in the volume of gray matter in the orbitofrontal, medial prefrontal, temporal and parietal cortex, ventral striatum and hippocampus; decreased glucose metabolism in limbic structures and prefrontal cortex. The greatest changes in depression are found in the hippocampus.

Disturbances in neuronal plasticity in depression are associated mainly with hyperreactivity of the hypothalamic-pituitary-adrenal system with hyperactivity of corticotropin-releasing factor, adrenocorticotropic hormone and cortisol, which leads to a decrease in the synthesis of brain-derived neurotrophic factor and changes in phospholipid metabolism. The main neurotrophic peptide in the body, brain-derived neurotrophic factor (BDNF), is responsible for neuroplasticity processes, including axon growth, increase in the number of synapses and cell survival. Stress and increased levels of glucocorticoids reduce both the content of this neuropeptide in the body and the neuroplasticity of the brain, including the ability for neurogenesis.

It is important to note that sleep-wake cycle disorders occupy one of the leading places in depression. Chronobiological mechanisms, in particular desynchronization of the circadian rhythm with the sleep-wake cycle, play an important role in the pathogenesis of depression and can lead to its prolongation, acceleration of phase formation and worsen the prognosis of the disease in general.

German researcher M. Papousek put forward as a hypothesis explaining the development of depression theory of phase advance of circadian rhythms. In particular, desynchronization of the sleep-wake rhythm and the temperature circadian rhythm is detected, a shortening of the latent period of sleep by a relative increase in paradoxical sleep in the first cycle. According to this theory, depressive episodes develop as a result of certain life events that cause disturbances in rhythms such as eating time, work routine, social needs, interpersonal relationships, which, in turn, lead to disturbances in the body’s ability to maintain stable biological rhythms, especially sleep rhythms. wakefulness and rhythms of psychomotor activity, wakefulness and appetite.

So, to summarize the above data, we can say that all of the above theories of the development of depression are most widespread and play a significant role in the development of depression, but they cannot completely explain the features and pathogenetic mechanisms of this disease. The lack of a single coherent theory of the development of depression and, accordingly, more advanced treatment methods constantly stimulates research interest, which in recent years has been aimed at searching for more accurate biological mechanisms (markers) of the disease, allowing one to find more effective treatment methods.

CHAPTER 2. A look at depression from the perspective of issiidiology

2.1. Causes of depression

What is the internal cause of depression, what does it mean for the general activity of the human psyche, how does it develop - science still does not have clear answers to all these questions. The problem of depression is also addressed in the recently emerged system of knowledge about the universe and man - Iissiidiology. Along with expounding cosmological concepts of the universe, it also deeply studies the nature of man as an integral part of the universe. In particular, this knowledge explains the causes of various painful conditions inherent in human nature.

Depression in Iissiidiology is considered as a result of the active “projection” of low-frequency and highly inertial modes of existence into mid-frequency levels of perception, expressed at the level of experiences in the form of conflict, internal inconsistency of ideas, and at the level of biology in the form of disturbances in biochemical and hormonal dynamics in certain parts of the brain and organ systems. In depressive states, the personality psychomentally “falls out” for a long time into pre-Vallsian (low-frequency) processes, in order to consistently synthesize those of the identical (covarller) signs that are necessary to complete intra-qualitative transformations, to be able to carry out inter-qualitative synthesis at higher frequency (ampliative) levels.

In Iissiidiology, the word “pre-Dollsian” means a narrow limitation, a high degree of subjectivity in the perception of everything that happens within the individual himself and in the surrounding reality, which is explained by the insufficient number of covariate relationships between information fragments that form the psychomental activity of a given individual. That is, in other words, this is an intra-qualitative undersynthesis, the implementation of which occurs, including during depressive states.

What is meant by qualities? To put it briefly, these are information blocks of self-awareness, consisting of similar information fragments that differ from each other in certain characteristics specific to each of them. We are constantly engaged in the synthesis of different quality information flows, structured by smaller information fragments or aspects. The synthesis stage begins with the formation of intra-qualitative relationships between aspects of information that form one quality; As the interaspect synthesis is completed, the process of inter-qualitative synthesis is launched, that is, between groups of information. The higher the degree of inter-qualitative synthesis, the more qualitative experience each form of self-awareness has. That is, in human thinking, concepts (SFUURMM-Forms) begin to appear with clear signs of an already accomplished inter-qualitative synthesis of the most similar, identical (covarller) relationships of the Human (lluuvvumic) direction of development, which in Iissiidiology are presented as highly sensitive intelligence and highly intellectual altruism, expressed in the form of mercy, compassion, understanding, responsibility, openness, honesty, selflessness, love of kindness and the like.

Since the focal dynamics (perception, psychomental activity) of the majority of representatives of the collective consciousness of modern humanity still remains very active in the low-frequency (pre-Olls) range, then powerful, prolonged depressive states are a characteristic sign of those people who are long-term fixated on low-quality ideas (depletive SFUURMM-Forms), expressed as criticism, aggression, pessimism, and so on.

Deep stressful conditions that cause people physical and mental pain, unbearable mental suffering, as well as all kinds of pathological changes in the functional activity of biological systems are the consequences of constant disharmony in the focal dynamics of people. That is, it is the negative form-images of severe psychomental states, the unfulfillment of low-quality desires, interests, all kinds of phobias that arise on the basis of existing experience, which completely depends on the degree of intra-qualitative synthesis, that are the causes of depression and prolonged stress.

2.2 Neurobiological changes during depression

Any of our thoughts and feelings (SFUURMM-Forms or ideas) are an information flow coming through photons, elementary particles, and then through the atomic-molecular structure of DNA. The level of ideas a person fills his information space with is the same quality of information that will structure the cells of his biological organism. Accordingly, by changing the direction of their thinking, everyone can significantly influence the state of the processes occurring in the biological body, and, first of all, the dynamics DNA and the brain, since the information in our body and in general in any proto-form (plants, animals, and so on) is deciphered by gene shape-creators of DNA, which are connected with the central nervous system, or more precisely, with such parts of the brain as pituitary gland, pineal gland, hypothalamus, correcting all the dynamics of bio-creators by producing hormones and neurotransmitters.

All activities of form-creators are mainly carried out through the wave part of DNA. Transmission of information from the DNA of cells occurs through neural connections in a wave manner, with the help of neurotransmitters to the brain (hypothalamus, pituitary gland, pineal gland, amygdala, hippocampus), and it, in turn, begins to distribute this information using its connections, connects the endocrine system, which regulates the cardiovascular, autonomic, digestive and other systems. In the above-mentioned parts of the brain, information for mental and vital processes characteristic of humans is modeled and recoded, and “long-term memory” is located - individual ODS - that is, the information we individually receive throughout our lives is archived. They represent centers for adjusting SFUURMM-Forms of various protoform directions of development and are the “command post” of form-creators.

As mentioned above, the physiological, as well as pathological functioning of bio-creators, to one degree or another, depends on our thoughts, our feelings, our experiences. But, on the other hand, chemical substances (hormones, mediators, etc.) released by the biological system also still significantly affect the quality of mental processes. For example, let’s take oxytocin, a hormone that harmonizes the body’s biochemical processes. It is, as it were, a unifying, reinforcing mechanism for the coordinated work of bio-creators. Accordingly, all processes occurring at the level of bio-creators, due to the influence of this hormone, are more harmonious, harmonious, the body does not experience stress, and we feel good, we are in a blissful, positive state.

And if our psychomental activity is more structured by negative, grossly sexual - depletive - experiences, then there is an increased release of adrenaline or cortisol, which excite aggression, undermine biological systems, that is, lead to stressful conditions in neighboring organs, which leads to powerful loads of the hematopoietic, respiratory , hormonal system. And this, in turn, leads to organic pathologies and, consequently, to the aging of the body, that is, to processes that force all other bio-creators to leave the state of symbiosis.

Prolonged sexual activity or, conversely, suppression of this level of desires also leads to depressive disorders. Disruption of the metabolism of sex hormones (estrogen, progesterone, oxytocin, testosterone, and so on) in the direction of its predominance or decrease contributes to the development of various kinds of pathologies, including cancer of the genital area, including a consequence of a high degree of activity of gross sexual interests.

The hormone cortisol (in a healthy body, daily secretion is about 20 mg of cortisol, but under stress, the adrenal glands release it an order of magnitude more), excessively produced in the body during prolonged psycho-stress, is a very active realization form of SVUULL-VVU copies, that is, low-frequency (negative), including grossly sexual forms, desires, reactions; it acts as an immune poison (the immunosuppressive effect of cortisol is fundamentally inexplicable for doctors who do not yet have this information), killing protective cells - lymphocytes and interfering with their complex interaction with each other, reducing immunity.

This information explains the relationship between the predominance of pre-Ollsian (low-frequency) processes and the high content of destabilizing hormones in the body of a patient with depression. That is, excessive production, for example, of cortisol during depression is caused by certain form-images, which are implementers and at the same time products of destructive (depletive) mental processes occurring in a given period.

For a more in-depth understanding and awareness of the importance of the influence of the quality of psychomental activity on the occurrence of certain changes, both in the consciousness and in the biological body of a person, I would like to explain the essence of low-, medium- and high-frequency processes occurring in our self-awareness in connection with activity the main areas of the brain, which are the “reptilian complex” (reptilian brain), the limbic system and the “new brain” - the neocortex.

For high-quality perception of any information, a coordinated interaction of the right hemisphere of the brain with the left, the form-creators of its evolutionarily “early” departments with the creators, respectively, of the “later” ones, is required. During human evolution, the first brain stem to develop is called the reptilian brain. The “reptile complex” houses the subconscious—the hereditary, genetically summed experience. This system includes: the spinal cord, medulla oblongata, pons (brain stem), cerebellum (connected with the neocortex), midbrain. The reptilian brain, as the oldest part of the brain, is the weakest component of intelligence. The activity of the reptilian brain is associated with the instinct of survival, with the desire to procreate. This part of the brain controls functions such as obtaining food, seeking shelter, and defending its territory. When the reptilian brain becomes dominant, the person loses the ability to think at higher levels.

Next, the reptilian brain is surrounded by a very complex limbic system, called the “mammal brain.” This area of ​​the brain is located significantly higher on the evolutionary ladder than the reptilian brain and is present in all mammals. The group of centers that make up the limbic system is associated with complex aspects of emotional expression. She is responsible for the emotional assessment or analysis of the content of various objects and life lessons, the manifestation of these emotions in external behavior controls biorhythms, the manifestation of hunger, controls blood pressure, sleep, metabolism, heart rate, and the state of the immune system. The need for food and sex, the emotions of joy, anger, sadness and love are born within the limbic system. The mechanism for controlling the five senses and transmitting the received information to the neocortex is also included in its functions. The limbic system contains the contents of the subconscious (reptilian brain) and information from the waking consciousness (neocortex). With the development of the neocortex, the limbic system of the human brain has decreased in size, and is now less developed than, for example, in animals. But, despite these changes, this area of ​​the brain still actively influences the human psyche. To manage our emotions and demonstrate appropriate and constructive emotional responses in all situations, we need to learn to use the capabilities of the limbic system of our brain.

The neocortex (“new brain”) is the evolutionarily last part of the brain. This zone is the most energy-information-capacious, universal and most involved in brain functions. The neocortex, as the center of higher mental activity, carries out the highest level of coordination of the brain, that is, higher neuropsychic activity. It also perceives, analyzes, and sorts messages received from the senses. It has the functions of regulating reasoning, thinking, decision-making, realizing a person’s creative abilities, and implementing the appropriate control of motor reactions and speech.

The “new brain” is divided into 5 parts: the frontal lobe, the temporal lobe, the parietal lobe, the main posterior lobe and the cerebellum (closely related to the “reptilian complex”).

The main task of forming high-frequency processes based on intellectual-altruistic ideas in the brain is performed by the prefrontal cortex of the neocortex, which is the most developed part of the brain. This part of the frontal lobe also contains the motor speech center, which for “right-handers” is in the left hemisphere, and for “left-handers” it is in the right hemisphere.

The frontal lobe has numerous connections with the thalamus and limbic system. Here, excitations are associated with various ideas and are then recognized as emotions. It is due to the growth of connections between sensors and emotional arousals that multilateral thinking develops - abstract ideas and combined judgments.

The dominant activity of the frontal lobe of the neocortex is associated with high-frequency, that is, highly intellectual and altruistic human choices that contribute to the development of the perception system, the sensation of high-frequency vibrations of the universe, the awareness of intuitive experience, and, therefore, the use of it in one’s life creativity.

During human life, the form-creators of the brain need to process a lot of different-quality information, which is simultaneously projected into their configurations from different protoform directions (non-human, for example, animals, manifested in human self-consciousness in the form of a predominance of selfish interests), which structure everything around us information space. If this information is of a stable destructive nature, then the person seems to “fall out” with part of his current interests (foci) from the events of the surrounding reality and “falls” into what doctors and psychologists call depressive states. Long-term refocusing in one of the protoform directions contributes to a sharp change in some of the basic functions, electrical and magnetic relationships between the bio-creators of certain systems and organs. This leads to the emergence of pathological changes, that is, dissonant states between the bio-creators of those parts of the biological body, the dynamics of which have already moved to a greater extent in the protoform direction. These bio-creators have experience of effective interaction with other organs only in the range of manifestation of their proto-form, therefore, as part of the human form, their natural biochemical reactions inevitably create powerful tensor tensions due to the incompatibility of multidirectional functional activities.

The human body was not initially designed for such protoform activity, which is why the resulting tensors begin to appear in its functioning at the level of various painful symptoms, failures and disorders. This is reminiscent of what happens on a factory conveyor, when someone begins to perform some operation slower or faster than expected or makes a defect - then the well-functioning operation of all other parts of the system begins to malfunction: in some parts of the conveyor, downtime begins or , on the contrary, there are congestions, and in others it is impossible to complete what has been started.

In the human body, such disruptions primarily manifest themselves through temperature fluctuations, disturbances in the blood supply and endocrine system, water-salt balance, pain and inflammatory processes. These initial symptoms are a signal to the form-creators of the brain about an imbalance in the body. Then, in the patient’s self-awareness, ideas begin to intuitively arise that something needs to be done in order to get out of these states and refocus (shift, exit) into a normally functioning form, for example, a feeling of the need to repent of some of the things he has done misconduct or awareness of the enormous importance of some event that was incorrectly (negatively) perceived by them, or simply the desire to eat something to make up for the lack of some substances.

Depression as a process - this is additional processing, completion, additional synthesis of protoform information by finding higher-frequency motivations and making choices of the appropriate quality, which ends with exit (refocusing) into higher quality (ampliative) states. The completion of these processes can be subjectively judged by the ever-increasing degree of neutrality or positivism of your previously extremely negative or critical psychomental reactions to anything or anyone from the reality around you. A synthesis of this kind is necessary for the consistent implementation of the process of continuous “reprojection” of the general focal dynamics (transformation of interests, views, desires) into higher quality states (configurations).

2.3 The positive impact of depression from the perspective of science and issiidiology

Clinical depression is considered a terrible disease that destroys a person’s life and psyche, but scientists have divided opinions on this matter.

Some experts believe depression is good for your health. “I believe that people who overcome depression become stronger. It can be a catalyst for survival: you look into the abyss and see the abyss,” says Marjorie Wallace, founder of SANE, a former sufferer of depression herself.

In his book Losing Sadness: How Psychiatry Turned Normal Sadness into Pathological Depression, New York University's Jerome Wakefield argues that depression can push us to make positive changes in our lives, help us learn from our mistakes and understand our desires.

According to Dr Paul Kidwell, an expert in mental disorders at Cardiff University, depression can still be good for us because the mechanism for dealing with it has an evolutionary basis: depression encourages people to eliminate factors from their lives that cause chronic stress. “Although depression is a terrible disease and no one would choose to go through it again, it helps us be more realistic,” says the professor.

American psychiatrists from the University of Virginia conducted a number of studies and also came to the conclusion that depression also has a positive side. An experiment involving more than a hundred students showed that those participants who suffered from depression performed better on tests of thinking ability. What is curious: those students who did not experience depression before the experiment showed a noticeable level of depression after completing the tasks. Scientists have come to the conclusion that the thought process is in a certain way associated with depression, since it turned out that the need to deal with complex problems forces a person to concentrate and makes him much more serious. Thus, depression promotes the development of deeper, analytical thinking.

From the point of view of issiidiology, from the position of the growth of human self-awareness, depression is a very positive moment in his life, a very important turning point. Therefore, you don’t need to be afraid of depression, you just need to understand that this is a very important period for self-improvement. During this period, powerful formations of focal relationships and decoding of protoform information occur at low- and mid-frequency levels with the benefit of cultivating Human qualities (lluuvvumic direction). Also, at the same time, one develops skills in analyzing psychomental processes, the ability to promptly prevent protracted depressive disorders, and over time, the ability to bypass such deviations in the psyche and the functional activity of systems and organs.

CHAPTER 3. Methods for getting out of depression

The mechanism of the appearance and development of depression is still not completely clear to scientists, and, therefore, the treatment strategy has not been clearly defined. There are many theories about this, but none of them are generally accepted. Among them, three main theoretical models are the most relevant: psychoanalytic, behaviorist and cognitive. Treatment is based on these models.

Methods used in the treatment of depression can be divided into two large groups: medicinal And psychotherapeutic. In addition to the treatment itself, a significant role is given to prevention (increasing the overall stability of homeostasis, mental self-regulation, the ability to adapt during periods of possible exacerbations).

To the first group (drug treatment) include psychotropic drugs, mainly antidepressants. The principle of action of antidepressants is to correct the functioning of certain brain mechanisms, enhance the transmission of nerve impulses, regulate the concentration of so-called happiness hormones and prevent their destruction. But even correctly and reasonably conducted psychopharmacological treatment of depression turns out to be ineffective in 20-30% of cases. This dictates the need to use non-drug methods to combat depression.

To the second group include phototherapy (treatment with bright white light), sleep deprivation therapy, electroconvulsive therapy, climatotherapy (the dependence of some depressions on the season is used). But the first place here is occupied by psychotherapy - therapeutic effects using psychological methods (words, special settings, activities, non-verbal effects). Psychotherapy is the “art of useful conversation” with a joint search for productive ways of thinking about a problem and its resolution, emphasizing resources and solutions. The most commonly used psychotherapeutic approaches to treat depression are cognitive-behavioral, non-directive, psychodynamic, problem-focused, body-focused, and family-focused.

In Iissiidiology, all painful symptoms are considered only visible consequences, the main reason for which lies in a powerful imbalance of psychomental states. To get rid of these symptoms, it is necessary to make appropriate efforts to help balance mental and sensory processes and restore the functional activity of the whole organism. The greatest effect is achieved with radical intellectual-altruistic refocusing by eliminating any negative dynamics from them. For example, when we resolve a situation with openness, some kind of high-frequency aspiration, when, instead of being offended, we approach a person, hug him and sincerely try to show all the best, sincere feelings, that is, we open up, and thus create opportunities to jump over depression. Finding strength in spite of the inertia and viscousness of these processes, by making a radical decision of openness, high sensuality and intellectuality, we pull ourselves out of these long-term depressive states.

The ability to realize the true cause of some of the stable tensors - internal conflicts in relation to someone or something, long-term grievances or something else that contributes to the maintenance of destructive states in self-awareness, this is also one of the operating mechanisms for refocusing into those forms , where there was a cure for depression or any other illness.

That is, it is important to understand and remember that the process of healing from something is not a “repair” of functional disorders, but a search for better motivations for sustainable psychomental balancing and refocusing into their more ampliative (qualitative) configurations, whose bio-organisms are initially encoded in normal functioning. With the help of such methods, you can refocus into healthy configurations much faster than with drug treatment (which often negatively affects the functions of other healthy systems and organs).

All kinds of medications and preparations you take, manual and physiological manipulations, radiation and surgical operations are to a greater extent factors that help the form-creators of self-consciousness to more deeply and reliably establish themselves in the SFUURMM-Forms of a speedy recovery and, due to this faith (confidence), steadily direct the process of refocusing precisely in those scenarios where this goal has already been achieved.

According to Dr. Paul Kidwell, an expert in the field of mental disorders from Cardiff University, depression makes a person re-evaluate his entire life and the tasks in it, antidepressants are powerless in the fight against the disease unless a person gives up the lifestyle that provokes depression. Iissiidiology also believes that the way out of the most difficult life situations lies in improving the quality of one’s thinking and feeling, in increasing efficiency and in cultivating states of one’s own intellectuality and altruism, selflessness and goodwill, and optimism.

Gradually, as a person opens up more and more to the positive sides of his Life, negative reactions become less typical for him, and positive impulses become more constant, due to which his self-awareness, more and more deeply synthesized at lower (pre-Dolls, selfish) levels , carries out more and more dynamic refocusing into higher-quality configurations, and all life changes very much for the better over time.

Conclusion

Summarizing all of the above, I want to say that this area of ​​science needs more universal research methods and sources of knowledge that provide a more objective explanation of the development mechanisms and etiology of this type of mental disorder such as depression. I decided to compare scientific hypotheses with the consideration of this problem in Iissiidiology, because, in my opinion, Iissiidiology is precisely the knowledge that reveals the true causes of this pathology and the main neurobiological abnormalities that play a leading role in the pathogenesis of depression.

According to Iissiidiology, pathological changes at the level of all biological systems and organs during depression occur due to an overabundance of undeciphered information. The lower the levels this “loading” is, the greater the inertia, which requires more time to unload the entire biological system, especially such a specialized area of ​​the brain as the hypothalamus, which is busy adapting and correcting incoming information for psychomental processes characteristic of humans. That is, the hypothalamus is the upper level in the regulation of the secretion of all hormones, in other words, the “command post” that controls the functions of the body. An excess of protoform, that is, destructive information leads to hyperactivity of certain areas of the hypothalamic-pituitary system, which promotes increased secretion of the hormone cortisol, which indicates dysfunction of the adrenal cortex.

Thus, I believe that functional disturbances in the HPA axis during depression are caused by excessive activity in a person’s psychomental activity of both aggressive and non-positive, pessimistic ideas about oneself and the surrounding reality. This information is one of the modern explanations for the causes of functional disorders in the HPA axis that develop in most patients with depression.

According to the author of Iissiidiology: “Very often the reasons for depression are that you have already known yourself at previous levels, but you are fixated on them, lingered too long, and you have no incentive to live, no interest in life in a new manifestation of yourself, in new acts of self-discovery. You need to find moments through which you would begin to feel differently, to learn, to strive for something different, in this desire to find all the buzz, the meaning of life, the meaning of tomorrow. You need to direct all your attention and interest to some specific activity, begin to get to know yourself in it, and over time it will become a “stepping stone” in order to reach a new level of Creativity. This is the source of joy. While you are doing something, creating, it is joy. As soon as I stop creating, everything immediately gets sucked into the “swamp”, life loses its meaning.”

The more high-quality SFUURMM-Forms a person uses in his life’s creativity, the more universal and perfect properties (configurations) his brain will have. And the higher the functional capacity of the molecular structures of the brain, the better choices and decisions a person will be able to make.

In Iissiidiology, form-creators, bio-creators are considered as combinations of information relationships that form the basis of all psychomental activity, biochemical and biophysiological processes of a person. These information combinations are the basis for the formation and interactions of elementary particles, atoms and molecules that structure the entire surrounding reality.

Literature:

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2. Mosolov S.N. Modern biological hypotheses of recurrent depression. Journal of Psychiatry and Neurology 11, 2012, issue No. 2, pp. 33, 34.

3. Maslennikova E.V. Depression. Techniques for working with depression, 2006. Pp. 1, 2, 3.

4. Tiganov A.S., Kopeiko G.I. Brusov O.S., Klyushnik T.P. New in the study of the pathogenesis and treatment of endogenous depression. Journal of Neurology and Psychiatry, 11, 2012. Pp. 65, 66, 67. http://www.mediasphera.ru/uppic/Zhurnal%20nevrologii%20i%20psikhiatrii%20imeni%20S.S.%20Korsakova/2012/11/14/Nv_2012_11_2_065.pdf

6. Kochetkov Ya.A., Beltikova K.V., Gorobets L.N. Anabolic balance in depression: the effect of tianeptine. Journal of Neurology and Psychiatry, 10, 2006, p. 47. http://mniip-repo.ru/uploads/1361202146.pdf

7. Voznesenskaya T.G. Treatment of depression in neurological diseases. Journal "Farmateka" (for practicing doctors) 2013, No. s4-13

8. Krasnov V.N. Problems of modern diagnosis of depression. Journal of Neurology and Psychiatry, 11, 2012; Vol. 2

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17. Doctors have discovered the positive effect of depression.

19. S. Ilyinsky. Neurolinguistic programming. Thinking.

Depression is a heterogeneous disorder associated with various psychopathological subtypes and neurobiological and psychosocial etiological factors. However, patients have different responses to therapy.

This condition is characterized by a high level of comorbidity with other somatic and mental disorders, which significantly complicates the diagnosis of depression. Considering that early manifestations of the disease usually include various emotional, physical and cognitive symptoms, patients more often seek help from general practitioners.

Depression is considered one of the most common mental disorders with severe medical and social consequences. In Europe, 38% of the population suffers from some kind of mental disorder. So, according to statistics, the first place is occupied by anxiety disorders, the second by insomnia, and the third by depression. According to official data, the prevalence and incidence of depression in our country is very low. This may be due to the reluctance of patients to visit doctors due to painful manifestations, as well as the fact that society is not fully aware of the negative consequences of the disease and stigmatization towards persons suffering from a mental disorder.

Also not the least important role is played by the lack of awareness of general practitioners and diagnostic errors, as a result of which inadequate treatment is prescribed, or patients do not receive it at all. Thus, among people with depression in our country, only 6-9% receive adequate therapy. However, it is worth remembering that this disorder has serious medical and social consequences: the risk of suicide is 15%, while 90% of those who committed suicide suffered from depressive disorders. In addition, based on DALYs (the number of years of healthy life potentially lost due to premature death or disability due to disability or chronic disease), it was found that by 2030 depression will be in first place among diseases with potentially dangerous consequences.

Neurotransmitter dysregulation plays a major role in the pathogenesis of depression. In addition, the mechanism of development of depressive disorders is influenced by a decrease in brain monoaminergic transmission, oxidative stress, a decrease in neurotrophic factor, an increase in the level of pro-inflammatory cytokines, dysregulation of the hypothalamic-pituitary-adrenal system, etc. It should be remembered that with depression, disturbances occur in various metabolic systems: sympathoadrenal , renin-angiotensin-, immune and neurotrophic. According to neuroimaging studies, significant functional changes are observed in almost all areas of the brain.

The interaction of genetic mechanisms and environmental factors in each specific case determines the effectiveness and safety of therapeutic effects. All known drugs interact with blood proteins, enzymes, receptors, ion channels, and this connection, depending on genetic mechanisms, affects the rate of absorption, distribution, metabolism and elimination of the drug. These mechanisms also depend on age, the condition of internal organs, the characteristics of the internal environment of the body, etc. Genetic polymorphism of proteins involved in pharmacokinetics and pharmacodynamics forms the mechanisms of individual variability, effectiveness and safety of the drug. A patient's individual genomic biomarkers are used to predict what the response to therapy may be, the response to possible toxic side effects and other factors.

They are indicators of normal and pathological processes that reflect the body's response to therapeutic intervention and are associated with changes in the genome. These include neurotransmitter metabolites, neuroimaging data, electroencephalography results, levels of proinflammatory cytokines, hormones of the hypothalamic-pituitary-adrenal axis, metabolic markers and growth factors. Using individual biomarkers, it is possible to practically predict the possible response to therapy, the safety and effectiveness of the drug used, toxic effects, side effects, and adjust the dose.

Today, effective and well-tolerated antidepressants that are quite safe to use are widely available. Most psychotropic drugs are metabolized in the liver by cytochrome P450, which results in low and high metabolic activity.

Treatment of patients is aimed not so much at establishing remission, but at functional recovery, at the patient’s social integration and at maintaining social activity. Help for a patient with depression should be provided comprehensively and contain pharmacotherapy, psychotherapy, non-drug methods, and should also include educational programs for patients.

When choosing an antidepressant, the patient’s experience, clinical features of the disease, professional knowledge, as well as the cost and availability of the drug are taken into account, since these criteria can be decisive for the patient. Typically, evaluation of the effectiveness of the drug begins in the second week of therapy; if a response to therapy is not observed, it is recommended to increase the dose, prescribe an additional drug, or replace it with another. In cases where there is no response to therapy, it is proposed to reconsider the diagnosis, assessing psychosocial factors, exclude alcohol and drug addiction, determine the level of antidepressant in the patient’s blood plasma, the degree of compliance and the presence of resistant depressive disorder.

Among the main antidepressants, there are first- and second-line therapy drugs. Recently a new drug appeared - desvenlafaxine. This is a dual-action drug, which is the most active metabolite of venlafaxine, is not metabolized by cytochrome P450 and has a low potential for drug-drug interaction. In addition, compared to venlafaxine, it has more pronounced noradrenergic activity, which allows its use in fibromyalgia and depressive disorders with pronounced somatic manifestations. According to randomized, double, placebo-controlled studies, the drug has shown its effectiveness even at an initial dose of 50 mg, which is therapeutic. Unlike other antidepressants, desvenlafaxine does not lead to weight gain, and on the contrary, weight often decreases. The starting dose of desvenlafaxine is 50 mg and the maximum daily dose is 100 mg.

For depressive disorders, they try to use safe treatment methods. Modern pharmacological strategies are based on the use of active metabolites of antidepressants that do not enter into active interactions, which is a promising direction for increasing the effectiveness of antidepressant therapy.

In order to optimize the early stage of treatment, the possibility of functional recovery, as the main target of treatment for depression, must be considered from the point of view of the evidence base. An important factor is the tolerability of the drug, because a certain proportion of patients refuse to take antidepressants precisely because of adverse reactions, which can lead to the formation of resistant forms of the disease. At the same time, functional recovery in the modern understanding is considered not only as a regression of symptoms, but also a complete restoration of the patient’s social and professional activity. However, in practice, functional recovery always lags behind symptomatic improvement.

In psychiatry, there are compensatory rehabilitation options, when the patient can function despite the presence of individual symptoms. To achieve early, optimized therapy, monitor disease manifestations and function early in treatment, starting at weeks 1–4. They also ensure that the patient is not receiving ineffective therapy, which could delay recovery and increase the risk of continued functional deficits. Early improvement of more than 20-30% from baseline in depression scores at 2-4 weeks is associated with response to treatment and remission at 6-12 weeks. If the patient does not improve after 2-4 weeks of therapy, the guideline recommends increasing the dose of the antidepressant (if tolerated) or switching the patient to another antidepressant (if intolerant). If the prescribed drug does not work in the early stages of therapy, it is not advisable to increase its dose in the future, as this will increase the risk of side effects. It is important to understand the level of effectiveness of an antidepressant in the initial stages of treatment, since drug withdrawal at this stage is easier to tolerate.

The universal and most effective tool for screening, diagnosing, monitoring and determining the severity of depression is the Patient Health Questionnaire. To assess loss of performance, the Sheehan Disadaptation Scale (SDS) is used, which is used to determine impairments in work, school, social and family life. Thus, a total score exceeding 5 points indicates significant functional damage.

The effectiveness of treatment depends not only on the clarified purpose and methods of treatment, but also on the patient’s compliance with the regimen and duration of treatment, since the level of non-compliance is quite high. The main reasons why patients refuse to take antidepressants:

1) fear of weight gain;

2) lack of erection in men;

3) difficulties in achieving orgasm.

Today, many doctors agree that when eliminating depression, it is necessary to change approaches to treatment, take into account the individual characteristics of each patient, and try to achieve complete recovery. It is necessary to make the first attempt at treatment the best and most effective. In addition, it is necessary to remember about the interaction between medications, because it has a significant clinical impact on the choice of drug. At the moment, the drug Elifor (desvenlafaxine) is an effective antidepressant with convincingly balanced efficacy and tolerability, which can be recommended for the successful treatment of patients with major depressive disorder.

Catad_tema Depression - articles

Features of depression in neurological diseases

I.V. Damulin
Department of Nervous Diseases MMA named after. THEM. Sechenov, Moscow

Depression: epidemiology, risk factors, pathogenesis

Depression is considered one of the most common diseases, second only to arterial hypertension. Depression accounts for about 10% of all visits to a general practitioner. The main manifestations of depression are low mood and loss of interest in life or lack of pleasure in life. At the same time, patients with depression that does not have an organic cause often turn to specialists in various fields with complaints characteristic of various somatic diseases.

In the United States alone, the annual costs associated with depression exceed $40 billion; of which 17 billion are due to loss of ability to work. The prevalence of major depression in the general population is 2–4%, and up to 15% among hospitalized patients. If we include cases of subdepression here, then this figure will increase by 2–3 times. Women suffer from depression approximately 2 times more often than men (the frequency of episodes throughout life is 10–25% and 5–12%, respectively). The risk of depression increases with age; in older people it often occurs atypically and is not recognized in time. The prevalence of depression in the elderly is 10–20%; among patients with somatic and neurological diseases it occurs almost 2 times more often. Depression is characterized by a relapsing course - repeated episodes occur in approximately 60% of patients. Moreover, during treatment, partial remission is observed in 20–30% of cases, and repeated exacerbation within a year – in 40%.

In addition to age, risk factors for depression include a low level of education and low social level of the patient, lack of work, a history of depression, marital status (depression is more common in single people) and stressful situations. Heredity also plays a role: depression is more often observed in individuals whose family history contains indications of affective or panic disorders, as well as alcoholism. However, in elderly patients and the elderly, the genetic factor is less important than in young people.

Depression accompanied by somatic or neurological diseases further impairs quality of life and is more difficult to treat. In patients with cardiovascular diseases, depression increases the risk of disability and mortality. Arterial hypertension is accompanied by depression in approximately 30% of cases. Depression is observed in 15–20% of patients with myocardial infarction; mortality in this subgroup is 3.5–6 times higher than in patients without depression.

Patients with chronic neurological diseases are more susceptible to depression than patients with somatic pathology. Neurological diseases in which depression can occur are very numerous:

• Alzheimer's disease and other dementias;
• cerebrovascular diseases;
• extrapyramidal diseases - Parkinson's disease, Huntington's chorea, progressive supranuclear palsy, multisystem atrophy;
• chronic pain syndromes of various origins;
• multiple sclerosis;
• aphasia of various origins;
• space-occupying formations of the brain – tumors, chronic subdural hematoma;
• epilepsy;
• consequences of traumatic brain injury;
• encephalopathy of endocrine origin (with hypothyroidism, thyrotoxicosis).

The longer and more severe the neurological disease, the greater the degree of disability of the patient, the higher the risk of depression and its severity. In addition, a number of medications can cause depression (or increase its manifestations):

• antihypertensive drugs (reserpine, clonidine, β-blockers * and calcium antagonists);
• benzodiazepines;
• neuroleptics;
• barbiturates;
• sleeping pills and sedatives;
• chemotherapeutic agents (vincristine, vinblastine, etc.), interferon;
• H2 blockers (ranitidine, cimetidine);
• indomethacin;
• muscle relaxants;
• sulfonamides;
• corticosteroids;
• drugs that change the levels of sex hormones.

The problem of depression is closely related to the problem of suicide. Every third person experiences suicidal thoughts at least once in their life. For every suicide that occurs, there are almost 18 attempts, with women attempting suicide more often but committing it less frequently than men. The rate of suicide attempts in depression is 10 times higher than in the general population and increases as patients age. In the United States alone, almost 200 thousand suicide attempts are made per year, 30 thousand of which end in death.

The mechanisms underlying depression are being actively studied. It has been shown that not only the limbic system, but also cortical structures are involved in emotional reactions. Particular importance is attached to the frontal lobes of the brain. According to functional neuroimaging methods, the medial orbitofrontal cortex is activated during negative emotions, and the lateral orbitofrontal and lateral prefrontal cortex are activated during positive emotions. In depression, there is increased activation of the structures of the right hemisphere. There are several theories that attempt to explain depression from a neuropsychological perspective. It is assumed that the left hemisphere plays a greater role in the regulation of positive emotions, and the right hemisphere in the regulation of negative emotions. Moreover, the occurrence of depression is associated with dysfunction of both the left (mainly anterior sections) and the right (mainly posterior sections) hemispheres. Of particular importance in the pathogenesis of depression in the elderly is attributed to vascular damage to the subcortical-frontal connections with the occurrence, in addition to depression, of impaired executive functions, psychomotor retardation, and apathy.

Clinical picture of depression

The basis for diagnosing depression is the assessment of medical history and clinical data. The results of paraclinical examination methods (including neuroimaging) are not of great importance; they only help to exclude neurological or somatic causes of the disease. The detection rate of depression by general practitioners does not exceed 50%. To a certain extent, this is due to the low specificity of the clinical manifestations of this disease. For example, weight loss and increased fatigue can occur not only with depression, but also with cancer, diabetes and thyroid diseases.

There is a relationship between depression and complaints of increased fatigue in Parkinson's disease, multiple sclerosis, neuroinfections and cerebral vasculitis. Chronic fatigue syndrome occurs in 0.07–2.8% of people. More than half of patients with this syndrome and various somatic diseases also have depression. However, it should be emphasized that from a neurobiological point of view, chronic fatigue syndrome is not identical to depression.

Often, patients with depression complain of decreased appetite, lack of taste in food, and weight loss. Sleep disturbances may occur in the form of insomnia, frequent awakenings at night, which are accompanied by restlessness and aimless walking, early morning awakenings with the inability to subsequently fall asleep. Atypical manifestations of depression are the absence in some cases of complaints of low mood or the patient’s fixation on excitability or anxiety rather than low mood. Somatization of depression largely depends on ethnic traditions. Thus, in China, patients with depression rarely complain of a bad mood; much more often they complain of pain, dizziness and increased fatigue. Neuropsychological testing reveals memory and executive function impairments in patients with depression.

In neurological practice, the diagnosis of depression causes even more problems, not only because of the frequent occurrence of neurological symptoms and depression with damage to the central nervous system, but also because of the impact that various neurological diseases have on the emotional behavior of the patient. In particular, characteristic of parkinsonism slowness and impoverishment of movements, combined with disturbances in the rhythm and intonation of speech, makes it difficult to correctly assess the emotional status. Therefore, it is not surprising that in Parkinson’s disease, neurologists are able to identify depression only in a third of cases. This task becomes even more complicated in patients with severe cognitive impairment of various origins, aphasia or confusion

Difficulties in diagnosing depression may be due to the patient's behavioral characteristics. Elderly patients are characterized by a greater fixation on the manifestations of somatic diseases than on the characteristics of their mood. When visiting a therapist or neurologist (not a psychiatrist!), they focus mainly on problems associated with the existing disease (for example, Parkinson’s disease), and do not relate to emotional disorders. In some cases, this is due to the patient’s belief that such information is not of interest to a specialist. It must also be taken into account that many patients perceive the diagnosis of a somatic (even severe) illness much better than a mental illness. They often categorically reject such a diagnosis... The patient’s fixation on somatic symptoms often leads to the fact that he is prescribed many examinations, which, as a rule, do not reveal any pathology. On the other hand, a therapist or neurologist usually does not have time to listen to the patient’s sometimes very detailed story about his experiences, therefore Doctors try to avoid asking in detail about these problems.

The doctor’s belief that the vast majority of chronic somatic and neurological diseases must also exhibit symptoms of depression also hinders the timely and correct diagnosis of depression. In addition, a certain attitude of the doctor is required to identify problems in the psychiatric community, which can be difficult to implement in practice, given the patient’s frequent exaggeration of their somatic complaints or symptoms of increased fatigue.

Even having suspected depression, the doctor may avoid considering this problem so that the patient does not think that he is being caught in a simulation. It also happens that the doctor does not want to make such a responsible diagnosis, which transfers the patient from the category of somatic patients to the category of patients with a psychosomatic disease. Therefore, in some cases, instead of a diagnosis of depression, another diagnosis is given, for example, insomnia. Of course, a lot depends on the doctor’s experience in communicating with patients, his ability to correctly construct a conversation, the ability to take into account the patient’s nonverbal expression of his emotions, as well as on the doctor’s training in the field of psychiatry.

Depression and pain

Complaints of chronic pain, one of the most common “masks” of depression, deserve special attention. The combination of depression and chronic pain syndromes is observed in 50–60% of patients, and according to some data – even in a larger number of cases (65–100%). Pain leads to depression, and depression leads to the development of pain, including that caused by a decrease in the pain threshold. This vicious circle often underlies the chronicity of pain. Moreover, the localization of pain can be very different. In patients with migraine, a history of depression is 3 times more common. At the same time, depression increases the risk of migraines, and the presence of migraines increases the risk of depression. Depression can be associated not only with migraines, but also with other types of headaches.

It should be emphasized that depression itself does not cause pain in the absence of prerequisites - changes in joints, intervertebral discs, or organic substrate of headache. Depression only contributes to the maintenance and intensification of this pain, its chronicity. However, in some cases, chronic pain syndromes are manifestations of psychiatric diseases.

Depression and dementia

An important problem is the distinction between depression and so-called pseudodementia. Pseudodementia refers to disorders caused by functional psychiatric disorders (depression, schizophrenia, hysteria), which in their manifestations resemble dementia. In practice, significant difficulties often arise in these cases. Depression is the most important among the causes of pseudodementia (“depressive pseudodementia”, “cognitive impairment in depression”) - it is detected in 2-15% of patients referred for examination for dementia. The difficulties in differential diagnosis of dementia and depression are largely due to the similarity of the clinical manifestations of these two conditions, because both dementia and depression can manifest symptoms such as insomnia, apathy or motor retardation. Common symptoms of depression that mimic dementia include decreased memory, especially for recent events, and slowed thinking. However, despite patients’ complaints of “significant memory loss,” they tend to describe the details of their illness in some detail, and their impairments do not fully meet the criteria for dementia. Cognitive impairment often occurs over a period of days or weeks and is usually associated with significant life problems. In this category of patients, speech disorders and visual-spatial functions, dyspraxia are extremely rarely detected, and during neuropsychological testing, significant fluctuations in the severity of symptoms may be observed. EEG and neuroimaging usually do not detect changes.

The literature indicates that the administration of antidepressants improves cognitive function in pseudodementia. Therefore, the presence or absence of the effect of antidepressants in some cases helps in the differential diagnosis of depression (pseudo-dementia) and dementia. The dexamethasone test is not useful for distinguishing between depression and dementia.

Long-term observation of patients with pseudodementia showed that only a few of them subsequently develop dementia proper. However, there is evidence of a 50% risk of dementia within a few years in elderly patients with depression. Moreover, if MRI reveals diffuse changes in the white matter of the cerebral hemispheres (leukoaraiosis), then vascular dementia is more likely, and if diffuse cerebral atrophy and hippocampal atrophy are detected, Alzheimer's disease.

Depression in Alzheimer's disease and vascular dementia

Depression is often detected in patients with dementia. For example, in primary degenerative dementias, coexisting depression is observed in 20–30%, and in vascular (multi-infarct) dementia – in 25–30% of cases. This combination is typical for the initial stages of dementia. As the cognitive defect progresses, depression is less common in patients with dementia.

The presence of depression in Alzheimer's disease is a prognostically unfavorable sign of limited activity in everyday life, disability and early death. This category of patients has a significantly higher risk of episodes of agitation and psychosis. In pathological studies in patients with Alzheimer's disease and depression, a significant decrease in the content of biogenic amines is found in the locus coeruleus (norepinephrine), dorsal raphe nucleus (serotonin) and in the substantia nigra (dopamine).

Clinically, depression in Alzheimer's disease is characterized by anxiety, restlessness, and apathy; Often there is a feeling of despair. Sleep disturbances, loss of appetite, and weight loss are also noted. Despite suicidal intentions (in approximately 45% of patients), suicide attempts are rare. However, during pathological examination, changes characteristic of Alzheimer's disease are often found in suicides, although this disease was not diagnosed during life. Therefore, it is believed that the suicide rate in Alzheimer's disease is actually higher than previously thought.

Depression is believed to be more common and more severe in vascular dementia than in Alzheimer's disease. This especially applies to the subcortical variant of vascular dementia, associated with damage to small cerebral vessels supplying the deep parts of the hemispheres. This may be due to the significance of damage to the subcortical-frontal pathways in the genesis of cognitive and emotional disorders.

Depression in strokes

Depression is detected in 30–50% of stroke patients. At the same time, the difficulties of diagnosing depression in this category of patients should be taken into account. In some cases, overdiagnosis occurs, since symptoms that mimic depression (decreased appetite, sleep disturbances, sexual dysfunction) may be due to the underlying disease. On the other hand, assessment of the emotional sphere in this category of patients is complicated by the presence of disorders of higher brain functions (in particular, aphasia). Because of this, depression can go undetected.

As a rule, depression is observed in patients with more severe motor and cognitive defects. In its phenomenology, it does not differ from idiopathic depression, with the exception of a more pronounced slowness of psychomotor reactions. The pathogenesis of depression in acute cerebrovascular accidents is multifactorial in nature, and it is assumed that the mechanisms of development of depression after a stroke vary depending on the duration of the disease.

The location of the stroke is of great importance. Damage to the left frontal lobe is more likely to lead to depression than damage to other parts of the left and right hemispheres (including the frontal areas). In addition, the onset of depression is more often accompanied by damage to the subcortical parts of the left rather than the right hemisphere, which is associated with disruption of the ascending monoaminergic pathways. However, these data are not confirmed by all authors, and currently this problem is being actively studied. A stroke localized in the region of the caudate nucleus often leads to depression. Other risk factors include the size of the ischemic lesion, a history of previous stroke, the presence of cerebral atrophy, age and female gender.

Depression in Parkinson's disease

Despite the assertion of James Parkinson, made in 1817 when he first described the “shaking palsy,” that intelligence is not affected in this disease, at present the presence of cognitive impairment and depression in Parkinson’s disease is beyond doubt. Depression is detected on average in 45% of patients with Parkinson's disease, but this figure varies depending on the criteria and study designs between 4 and 70%. Depression is more common in younger patients.

Typically, in Parkinson's disease, depression is not pronounced and is often accompanied by anxiety (in almost a quarter of cases). Diagnosing depression in Parkinson's disease can be difficult, since many of the symptoms characteristic of it are also observed in Parkinson's disease itself - slowness of movement, sad appearance, apathy, attention problems, insomnia, weight loss. Therefore, physician caution is necessary in diagnosing depression in patients with this disease. In some cases, depression and anxiety may occur even before the development of extrapyramidal motor disorders characteristic of Parkinson's disease. Patients with more severe cognitive impairment also have more severe depression. Despite suicidal intentions often expressed by patients, suicides are rare.

The pathogenesis of depression in Parkinson's disease is associated with damage to monoaminergic neurotransmitter systems and frontocortical dysfunction. This is confirmed by data from pathomorphological studies: with a combination of Parkinson's disease and depression, pronounced changes are found in the area of ​​the locus coeruleus (noradrenergic system) and the raphe nucleus (serotonergic system). In patients with predominantly right-sided symptoms and with a right-sided onset of the disease (i.e., with a pathological process predominantly localized in the left hemisphere), depression is more common than in patients with predominantly left-sided symptoms and a left-sided onset.

Depression in multiple sclerosis

Depression is the most common behavioral disorder in multiple sclerosis; it is detected in almost half of patients, and in 20–25% of patients it is so pronounced that it requires treatment from a specialist. Depression may precede the clinical manifestation of multiple sclerosis, and its severity correlates with the severity of the disease and increases during periods of exacerbation. Moreover, more significant disorders are observed in patients with predominant damage to the temporal lobes according to MRI data. Until now, it is not clear whether the occurrence of depression in multiple sclerosis is associated with the disability of patients or whether depression is one of the manifestations of central nervous system damage in this disease. The latter assumption seems more likely. In particular, data from epidemiological studies indicate a higher prevalence of depression in multiple sclerosis than in such disabling diseases as amyotrophic lateral sclerosis and rheumatoid arthritis.

Depression in epilepsy

The prevalence of depression among people with epilepsy is 4–5 times higher than in the general population, and it is more common in men than women. Depression is observed in 55–60% of patients with epilepsy, but in almost two thirds of cases it remains unrecognized, and patients do not receive the necessary treatment. In addition, many doctors, even if indicated, do not prescribe antidepressants, fearing that they may lower the seizure threshold.

The importance of depression in epilepsy is also evidenced by the fact that among patients with this disease, the suicide rate is 5 times higher than in the general population. Moreover, depression is not only often detected in patients with epilepsy, but may precede its occurrence. It is assumed that there are common pathogenetic mechanisms of these two conditions, based on mediator disorders. In particular, the occurrence of depression in epilepsy is associated with pathology of the serotonergic, noradrenergic, dopaminergic and GABAergic systems. It is possible that in 11–15% of patients, depression is associated with iatrogenic folate deficiency, which can develop while taking antiepileptic drugs.

It is assumed that convulsive seizures are a kind of analogue of electroconvulsive therapy and therefore, in some patients, the occurrence of an epileptic seizure reduces the likelihood of developing depression. Conversely, a decrease in seizures is accompanied by an increase in the risk of depression (according to the “forced normalization” mechanism).

The combination of epilepsy and depression may also be due to genetic factors, since more than 50% of patients have a family history of diseases accompanied by mood disorders.

Patients with depression and epilepsy are characterized by periictal episodes of agitation. In 15% of patients, manifestations of depression may be part of the prodromal period of an epileptic seizure. Often, several hours (and sometimes days) before a seizure, dysphoria, irritability, and anxiety are noted. These symptoms become more severe in the 24 hours before the seizure. Postictal episodes of depression are usually accompanied by more pronounced postictal cognitive defects. In the interictal period, mood disorders are detected in 9–22% of patients; in their manifestations they are very diverse (major depression, dysthymia, bipolar disorders). Often, depression in this period occurs atypically, with episodes free from manifestations of depression lasting from several hours to several days.

A higher incidence of depression is observed in temporal and frontal lobe epilepsy (from 19 to 65% of cases), as well as in patients whose epilepsy is difficult to treat. In the latter case, the quality of life of patients often suffers more from the presence of depression than from the frequency and severity of epileptic seizures. Data that depression is more often observed with left-sided localization of the epileptic focus are contradictory.

Phenobarbital can cause depression; Suicidal attempts may occur during treatment with this drug. Depression may be associated with primidone, tiagabine, vigabatrin, felbamate and topiramate. Even drugs such as carbamazepine and valproate, which have antidepressant properties, can sometimes cause depression, although this occurs less frequently than with other antiepileptic drugs. In addition, lamotrigine and gabapentin have antidepressant effects, as does vagus nerve stimulation. It is interesting to note that the onset of depression in epilepsy can be triggered by the withdrawal of carbamazepine, valproate or lamotrigine.

Treatment of depression

The first question that arises for a neurologist or general practitioner is how much drug treatment using antidepressants is necessary for the patient. In a significant percentage of cases when emotional disorders are caused by external causes, depression is transient and regresses on its own. Often, a good effect can be obtained with the help of psychotherapy, which, if necessary, can be supplemented with antidepressants, however, the effectiveness of such a therapeutic approach requires further study. It should be noted that even with moderate depression, a positive effect from placebo is observed in a third of cases. On the other hand, often patients with depression do not receive the necessary treatment without proper reason. According to some reports, correct treatment is carried out only in 10–30% of cases.

The question of starting drug therapy becomes relevant if symptoms persist for 2–4 weeks. There are two more situations in which the tactics of monitoring a patient without drug intervention is erroneous. First: if the doctor is sure that the patient has been depressed for a long time. Most patients can fairly accurately identify the moment when they began to experience symptoms of depression (usually in connection with an emotional experience). Second: if the severity of the disorders is very significant and the disease threatens the life or health of the patient. This is not limited only to cases where the patient expresses suicidal intentions - urgent intervention is also required in situations where the patient refuses water and food or stops moving. The importance of timely diagnosis of cases of depression that threaten a suicide attempt is confirmed by the fact that more than 40% of elderly patients with depression who made a suicide attempt were seen by a general practitioner within a week before. Thus, the presence of suicidal intentions in a depressed patient is the basis for prescribing antidepressants. It is desirable that in addition to the main effect, the antidepressant also has a sedative effect.

To treat depression, drugs of different groups are used - monoamine oxidase inhibitors (MAOIs), antidepressants (tricyclic and tetracyclic, dopaminergic, selective serotonin reuptake inhibitors, selective serotonin and norepinephrine reuptake inhibitors, selective serotonin reuptake stimulators). The use of herbal remedies is recommended for the treatment of mild depression, but the effectiveness of this type of therapy has not yet been confirmed.

MAO inhibitors

Among the MAO inhibitors, selegiline is used in neurological practice. This drug at a dose of 20–40 mg/day (maximum 60 mg/day) has antidepressant properties, however, when used in such doses, it loses its selectivity of action on MAO B. There is experimental evidence suggesting anti-apoptotic properties of low doses of selegiline.

General characteristics of antidepressants

These drugs are effective in 50–60% of patients with depression. There are no significant differences in the effectiveness of antidepressants between young and elderly patients, but in the latter case the risk of adverse reactions is higher. In older patients, side effects may occur even when using “normal” doses of tricyclic antidepressants.

When dementia and depression are combined, antidepressants are also prescribed. These drugs are believed to be effective in both Alzheimer's disease and vascular dementia. However, it should be taken into account that the course of depression in these categories of patients may be of a fluctuating nature, i.e., an improvement in the patient’s condition may not be associated with taking antidepressants. In addition, one should take into account the surprisingly high effectiveness of placebos, in some cases comparable to the effectiveness of antidepressants. Unlike the treatment of psychosis in elderly patients with dementia, when minimal or even “homeopathic” doses of antipsychotics or benzodiazepines are used, standard, “adult” doses of antidepressants are used to treat depression in patients with dementia. The exception is tricyclic antidepressants, which are undesirable for use in dementia due to their anticholinergic effect. It is possible to prescribe antidepressants for chronic fatigue syndrome. The effect of this group of drugs is manifested by a decrease in symptoms of depression and an increase in activity in daily life, rather than a decrease in fatigue per se. However, no significant positive effect of therapy with serotonin reuptake inhibitors was noted, which may be due to the hypersensitivity of serotonin receptors present in this category of patients. Therefore, MAO inhibitors and tricyclic antidepressants are more preferable (the latter can be effective in small doses).

To treat depression in Parkinson's disease, drugs of different groups are used, but preference is given to selective serotonin and norepinephrine reuptake inhibitors. Recently, dopamine agonists have been shown to be effective.

Since most antidepressants can cause epileptic seizures (at least theoretically), treatment is monitored especially carefully in patients with epilepsy. Despite the fact that some antiepileptic drugs have antidepressant activity, in the presence of depression additional prescription of antidepressants is required. Treatment of depression in patients with epilepsy is recommended to begin with selective serotonin reuptake inhibitors. Because almost all antidepressants act on liver enzymes, careful monitoring of serum antiepileptic drug levels is necessary when prescribing them.

Treatment usually begins with low doses of antidepressants and gradually increases the dose based on clinical effect. The starting dose of the drug should be low in patients with liver and kidney failure, as well as in elderly people and the elderly. The dose increase is stopped when a therapeutic effect is achieved or when side effects develop. Dose titration is carried out when prescribing tricyclic antidepressants, and serotonin reuptake inhibitors can be immediately prescribed in a therapeutic dose. Combined treatment with two antidepressants is undesirable in the practice of a therapist or neurologist, and it is also associated with the risk of side effects, sometimes quite significant.

The effect of antidepressants usually does not appear immediately, but after several weeks (usually from 3 to 6). After regression of depression symptoms, therapy is continued for 4–5 months. If the effect of treatment does not appear after 6–8 weeks, switch to an antidepressant of another group. It is important to emphasize that in most cases the lack of effect is not due to true drug resistance, but to an insufficient dose or short duration of therapy, as well as non-compliance with medical prescriptions.

When choosing a drug, you need to find out from the patient whether he has previously taken antidepressants and what their effect was. The effectiveness of tricyclic antidepressants and serotonin reuptake inhibitors is almost the same, but the latter have less pronounced side effects in case of overdose. Drugs of these groups are used to treat chronic pain syndromes, which is based on their ability to modulate the activity of neurons at the spinal level due to effects on descending noradrenergic and serotonergic pathways. With postherpetic neuralgia and diabetic neuropathy, in 50–90% of patients, during treatment with antidepressants, the pain intensity decreases by at least 2 times. Good results were also observed for atypical facial pain and post-stroke pain. It is assumed that the analgesic effect of antidepressants is different from their main effect on depression. In addition, this effect occurs much faster (after 1–7 days).

When deciding whether to prescribe a particular drug, it is necessary to compare the expected effectiveness of the antidepressant with the possible risk of side effects. Along with being highly effective, tricyclic antidepressants are characterized by a number of side effects (anticholinergic, hypotensive), so drugs with better tolerability are more preferable. In addition, most tricyclic antidepressants cause weight gain. During therapy with drugs of this group, patients may complain of dry mouth and constipation. They may experience orthostatic hypotension and dizziness, which increases the risk of falls and fall-related fractures. Another unfavorable property of these drugs is their effect on cardiac conduction, which must be taken into account in patients with arrhythmias.

Serotonin reuptake inhibitors

Currently commonly used are fluoxetine, paroxetine, sertraline, fluvoxamine and citalopram, which have a wide range of indications including depression and anxiety, are easy to dose and have little toxicity even at high doses.

Because all of these drugs, with the exception of fluvoxamine, require only once daily dosing and are generally well tolerated, they are first-line drugs for the treatment of depression. These antidepressants are especially preferred in situations where depression is accompanied by aggressiveness or impulsivity. However, in 40–80% of cases, sexual dysfunction may occur while taking them. Patients may complain of gastrointestinal disorders. Also, when using drugs in this group, sleep disturbances may occur, which usually regress after one week of therapy. In addition, this group of drugs is characterized by the occurrence of general weakness and increased fatigue.

Recently, the question of the connection between suicides and the use of selective serotonin reuptake inhibitors (as well as tricyclic antidepressants) has been clarified. Despite the existing opinion about the ability of these drugs to reduce weight, in some patients body weight increases. Decreased dopamine levels, secondary to effects on different 5HT2 receptor subtypes, may exacerbate parkinsonism and impair concentration, which is sometimes mistaken for depression. Several cases of late hyperkinesis have been described with long-term therapy with serotonin reuptake inhibitors. Although these drugs relieve migraines, in some cases they can provoke severe attacks of this disease. In addition, serotonin reuptake inhibitors are not as effective for chronic pain as tricyclic antidepressants.

Azafen

The use of selective serotonin reuptake inhibitors is so popular not so much because of their effectiveness (in most cases they are inferior in effectiveness to tricyclic antidepressants), but because of the lower risk of side effects. Thus, it is preferable to use drugs that are quite effective and at the same time safe. In addition, it is advisable to choose drugs that are familiar to both the patient and the doctor. In Russia, one of these drugs is Azafen (pipofezin), a tricyclic antidepressant, which differs in structure and mechanism of action from other representatives of this group of drugs.

Azafen does not have anticholinergic properties, does not affect MAO and does not have an adverse effect on the cardiovascular system. In addition, this drug improves sleep; in this case, subsequent drowsiness does not occur.

The mechanism of action of Azafen is associated with non-selective inhibition of serotonin reuptake and an effect on the noradrenergic system. As a result of its use, the levels of these mediators in the central nervous system increase. In addition, Azafen has anxiolytic and sedative properties; it has also been shown experimentally to suppress aggressive behavior.

Features of the therapeutic effect of Azafen are:

• combination of antidepressant and anxiolytic effects;
• ability to normalize sleep;
• lack of anticholinergic effect;
• good tolerability combined with high efficiency.

These properties of Azafen allow it to be widely used for the treatment of depression of various origins, including in elderly patients, with cardiovascular diseases, glaucoma, and prostate pathology. Azafen is used for pain syndromes in patients with depression resistant to symptomatic therapy. Treatment begins with Azafen at a dose of 25–50 mg/day in 2 divided doses, gradually increasing it to the optimal dose of 150–200 mg/day in 3–4 divided doses. The duration of the course is 1–1.5 months. When a therapeutic effect is achieved, the dose is gradually reduced and switched to maintenance therapy (25–75 mg/day). Azafen is well tolerated; in some cases, while taking it, headaches, dizziness and nausea, as well as allergic reactions, may occur. Essay

Features of depression in neurological diseases
Depression is an extremely common illness. It often accompanies somatic and neurological diseases and further worsens the quality of life and is more difficult to treat. At the same time, neurological patients are more susceptible to depression than patients with somatic pathology. For the drug treatment of depression in neurological patients, antidepressants of different groups are used: tricyclic, tetracyclic, selective serotonin reuptake inhibitors, etc. Preferred drugs are not only effective and safe, but also well known to the patient and the doctor. These requirements are largely met by the tricyclic antidepressant Azafen (pipofezin). Unlike other tricyclic antidepressants, Azafen combines antidepressant and anxiolytic effects, lacks anticholinergic effects, normalizes sleep and is well tolerated.

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