MXPA99010411A - A method for the treatment of mental illness in mammals and a composition therefor - Google Patents

Abstract

The invention relates to a method for treating a mammal suffering from mental illness induced by propagation of stress, said method comprising the step of removing or diminishing the tone of the endogenous alpha-2C-adrenoceptors in the central nervous system of said mammal. The invention relates further to pharmaceutical compositions useful for said treatment.

Description

A METHOD FOR THE TREATMENT OF MENTAL DISEASE IN MAMMALS AND A COMPOSITION FOR HIMSELF FIELD OF THE INVENTION This invention relates to a method for the treatment of mental illness in mammals and compositions therefor. More specifically, the invention relates to methods and compositions useful for removing or decreasing the tone of endogenous alpha-2C-adrenoceptors in the central nervous system. BACKGROUND OF THE INVENTION The publications and other materials used herein to illustrate the background of the invention, and in particular, cases to provide additional details regarding the practice, are incorporated for reference. Conventionally, it has been found that the antagonists of the fa-2-adrenoceptors, such as yohimbine, are anxiogenic (1). Three subtypes have been discovered in humans, mainly alpha-2A-, alpha-2B-, and alpha-2C- adrenoceptors. A fourth subtype, an al-fa- 2D-adrenoceptor, is known in rats and bovines. According to the literature, the majority of known fa-2-adrenoceptor antagonists are not specific to any true subtype (alpha-2A to alpha 2-D). As examples of such non-specific antagonists of fa-2D-adrenoceptor there may be mentioned rauwolscine, yohimbine, idazoxan, atipamezole and RX821002 (reference 6, Marjamáki et al.). However, because the subtypes of alpha-2 -adrenoceptor have a discrete pattern of distribution in the brain (2) so that it appears that the al-2 C-adrenoceptor is distributed throughout the limbic system (a complex area of the brain related to conditions and other mental functions), it is hypothesized that a behavioral response of an alpha-2-adrenoceptor subtype C selective antagonist would be different from that of a non-selective subtype. OBJECT AND SUMMARY OF THE INVENTION The object of the present invention is to provide a method for treating a mammal suffering from mental illness induced by the propagation of stress, particularly a mental illness clinically expressed as anxiety, stress, post-stress disorder. traumatic, affective depression, anhedonine, allography, avolition, aggression or abnormality of cognitive function initiated by neuronal degeneration induced by stress. The object is also to provide a method for treating a mammal suffering from mental illness induced by the propagation of stress without substantially producing sedative or hypotensive effects or altering motor functions in said mammal. Thus, the present invention relates to a method for treating a mammal suffering from mental illness induced by stress propagation, said method comprising the step of removing or decreasing the tone of endogenous alpha-2C-adrenoceptors in the nervous system. central to said mammal. Furthermore, this invention relates to a pharmaceutical composition, or a derivative thereof, useful for the treatment of mental illness induced by stress propagation in a mammal, said composition comprising a therapeutically effective amount of an alpha-2-adrenoceptor antagonist. , which is selective for alpha-2C-adrenoceptor in combination with a pharmaceutically acceptable excipient. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the antagonism of dexmedetomidine-induced sedation (upper graphic) and of hypothermia (lower graphic) by previous administration of RX821002, a non-selective α-2-adrenoceptor antagonist for alfa - 2C-adrenoceptor (open bars) or MK-912, a selective fa-2-adrenoceptor antagonist for al-fa-2C-adrenoceptor (striped bars). Figure 2 shows the action of a pretreatment with MK-912 (full bar) or RX821002 (striped bar), as compared to the control, in the desperation-induced stress behavior of forced swimming in mice. Figures 3A and 3B show the action of the pre-treatment with MK-912 (full bar) or RX821002 (striped bar) compared to the control, in exploratory behavior in rats in a plus test - elevated labyrinth. Figure 4A and 4B show the effect of altering the function of al f a-2C-adrenoceptor on the level of expression of the gene in mice. Figure 4A shows the predisposition to stress-induced propagation of behavioral despair in transgenic mice overexpressing the fa-2C-adrenoceptor (striped bar) compared to their wild type (open bar) genetic controls. Figure 4B shows the predisposition to stress-induced propagation of behavioral despair in transgenic mice without expression of alpha-2C-adrenoceptor (striped bar) compared to their wild type (open bar) genetic controls. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new therapeutic approach for treating mental health disorder in mammals. The results to be presented below show that stress-induced anxiety and subsequent mental disorders can be prevented by means which remove or diminish the tone of the endogenous alpha-2C-adrenoceptors in the central nervous system of said mammal. The new therapeutic agents block al-2 C-adrenoceptors in the limbic system and remove or decrease the spread of the mental stress reaction, provide a new approach for protective anxiolytic therapy and a new method of treating patients suffering from of mental disorder clinically expressed as, for example, anxiety, stress, post raumatico stress disorder, affective depression, anhedoine, alogia, avolition, aggression or abnormality of cognitive function initiated by stress-induced neuronal degeneration. In addition, the alpha-2C-adrenoceptor antagonist selective for al-fa-2C-adrenoceptor used in combination with an anxiolytic, antidepressant or antipsychotic compound (such compound does not need to be a selective antagonist for fa-2C-adrenoceptor) , would be therapeutically beneficial by providing either an effective treatment to the patient resistant to said conventional therapeutic agents alone or by providing a synergistic action with said conventional therapeutic agents. The selective fa-2-adrenoceptor antagonist for the fa-2C-adrenoceptor and the second compound should preferably be administered to the patient during the same treatment period. More preferably, the α-2-adrenoceptor antagonist selective for alpha-2C-adrenoceptor and the second compound should be administered simultaneously. According to a particularly preferred embodiment, these compounds are administered from the same dosage form.

Such a combination therapy will allow the use of smaller doses of said compound and will substantially reduce its sedative effects, its disturbance in motor functionality and other adverse effects such as hypotensive effects. Suitable fa-2C-adrenoceptor antagonists selective for 2C-adrenoceptor are known in the literature. As examples, MK-912 (5) and BAM-1303 (12) may be mentioned. According to our own investigations, it has also been found that clozapine and risperidone have high selectivity for the fa-2C-adrenoceptor. Preferably, the antagonist must have a selectivity to the fa-2C-adrenoceptor of at least the same level as MK-912, ie, a preference of ten-fold for the alpha-2C subtype over the other alpha-2 - subtypes For the purpose of the invention, the alpha-2-adrenoceptor antagonist selective for al-a-2C-adrenoceptor or its pharmaceutically acceptable derivative (such as salt, ester or the like) can be administered by several routes. Suitable administration forms include, for example, oral formulations; parenteral injections that include intravenous, intramuscular, intradermal and subcutaneous injections; forms of transdermal or rectal administration. The required dose of the alpha-2C subtype selective antagonist compounds will vary with the particular condition to be treated, the severity of the condition, the duration of the treatment, the route of administration and the specific compound employed. The therapeutically effective dose for a particular compound may, for example, be established according to the method described in Experiment 1 below. In order to elucidate the role of a certain subtype of fa-2 -adrenoceptor, the pharmacological profile in the other subtypes should be fixed to the same degree. We have established such a method of experimental bioequivalence that allows the study of the profile differences of the a - 2 - antagonists that act on the fa - 2 - adrenoceptors that on alpha - 2A - adrenoceptors. Locu s coerul eu s is a brain nucleus that is almost exclusively occupied by the subtype at f-2A-adrenciceptor and mediates sedation induced by dexmedetomidine (an α-2-adrenoceptor agonist) (3). Later, work with transgenic mice indicated that the alpha-2C-adrenoceptor subtype contributes to the hypothermia induced by non-selective agonists of fa-2-adreceptors (4). We used this information to find a dose of a potential antagonist of subtype alpha-2C-adrenoceptor potential that antagonized equally the sedation mediated by alpha-2A-adrenoceptor in comparison with an antagonist of fa-2-adrenoceptor subtype non-selective . Information from the literature has indicated that MK-912 (also known as L-657,743) shows approximately a preference of ten-fold for al-a 2 C- subtype ipo over the other alpha-2-adrenoceptors (5) and that the affinity for alpha-2A and fa-2B-adrenoceptor is the same. In comparison with an antagonist of the f-2-adrenoceptor subtype non-selective RX821002 (with high affinity equally to all the subtypes of al-2 -aderenoceptor (6) we found that there is a clear difference in the ability of the antagonist to fa-2C-adrenoceptor MK-912 to antagonize dexmedetomidine-induced hypothermia compared to dexmedetomidine-induced sedation (see Figure 1 of Experiment 1 presented below), adjusting with the evidence obtained with the transgenic mice, based on the bioequivalence study from Experiment 1 below, we could conclude that both MK-912 and RX821002 at doses of 12.5 to 25 nmol / kg sc are equally effective in antagonizing sedation mediated by fa-2A-adrenoceptor but that their ability to antagonize mediated hypothermia by fa-2C-adrenoceptor is different, therefore, a dose of 15 nmol / kg sc of both drugs is selected to study the role of alpha-2C-adrenoceptor in model s animals that reflect behavioral changes induced by the propagation of stress. Experiment 1 The spontaneous motor activity of a single mouse was measured in a polypropylene animal cage (38 x 22 x 15 cm) with a transparent propylene cap by Photobeam Activity System (PAS), CageRack, San Diego Instruments, San Diego, USA). The temperature was measured by an electronic thermometer with a rectal test (Ellab A-S, CTD-M, digital thermometer, Roedovre, Denmark). The animals were injected with various doses of either RX821002 or MK-912, 20 min. before the injection of dexmedetomidine. Spontaneous motor activity was measured 20 min. after dexmedetomidine injection and body temperature was measured 30 min. after the injection of dexmedetomidine. The results are presented in Figure 1, which shows the antagonism of dexmedetomidine-induced sedation (upper graphic) and hypothermia (lower graphic) by previous administration of RX821002, the non-selective fa-2-adrenoceptor antagonist for the to fa-2C-adrenoceptor, (open bars) or MK-912, the alpha-2-adrenoceptor antagonist selective for al-fa-2C-adrenceptor (striped bars). The following four experiments were carried out in order to verify the role of alpha-2C -adrenoceptor in the propagation of tension in animals. Experiment 2 Action of the drug in the propagation of a state of behavioral despair in mice It has been observed that excessive or prolonged exposure of a stress-filled stimulus to an animal test propagates a state of desperate behavior. For example, a rat or mouse placed in a container full of water with no way to escape has an initial intense search for an escape but then the animal surrenders (behavioral despair) and initiates a motionless floating. Among the agents that in subacute treatment conventionally invest the desperation of stress-induced behavior are the antidepressant agents (7). Among the agents that conventionally inhibit the propagation of desperation of stress-induced behavior are anxiolytic agents, such as diazepam (a GABA-channel antagonist-benzodiazepine receptor compound) and dexmedetomidine. When studying different classes of mice, we found that a mouse NMRl class tolerates too much tension and the propagation of behavioral despair whereas a Balb / c class mouse is very sensitive, as described in the literature (8), to the tension and propagation of desperate behavior (see Table 1 below). In the NMR1 mouse it is observed as the amount of tension (ie duration of forced fading) 24 hrs. before the fading test, it affects the propagation of the behavioral despair state, reflected in active swimming time. However, the Balb / c class began to float almost immediately even without any forced swim period pre-test (Table 1) * The test was carried out as follows: Male NMR1 or Balb / c mice (Bomhol tgard, Denmark) they pre-stressed with different periods of 24-hr pre-test swimming. before swimming try. The mice were either drugged or experimentally naive. The pre-test forced swim periods were of duration 0, 1, 2.5, 5 or 10 min. The pre-test and test swimming were carried out in a 1 1 vessel (10 cm in diameter, 18.5 cm in height). The depth of the water was 8 cm, preventing the mouse from reaching the bottom. The duration of the swimming trial was 5 min., during which the forced swimming time was measured by a stopwatch. After the swimming periods, the mice were dried with a paper towel and kept under a heat lamp for approximately 15 min. The results are shown in Table 1. Table 1 Difference in NMRl and Bald / c class mice in the propagation of behavioral despair. Active swimming time (± SEM; seconds) after periods of forced swimming pre-test Class 0 min. 1 min. 2.5 min. 5 min 10 minutes .

NMRl 72 ± 13 49 ± 11 52 ± 21 16 ± 7.2 2.0 ± 0.88 Balb / c 1.3 ± 0.9 0.3 ± 0.3 ° 0 0 when NMRl mice were administered (15 min before forced swimming pre-test) with diazepa, they tolerated better stress-induced propagation of behavioral despair when measured Your active swimming time 24 hrs. after. However, dexmedetomidine has no influence on the propagation of behavioral despair (Table 2). When the Balb / c mice were administered (without a pre-test forced swimming period) with (15 min before the swimming test) diazepam or dexmedetomidine, they tolerated better the stress-induced propagation of behavioral despair (Table 2 ). These results indicate that these two classes of mice can be used to test different types of medical agents for their stress induced anxiolytic properties, such that NMR1 mice tolerate stress well but Balb / c mice are very sensitive to stress. In addition to these two classes, we found that the stress sensitivity of the mouse class C57BL / 6J (see below) is between the class NMR1 and class Balb / c mice. The tests were carried out as described above. The male NMIR mouse (B &K, Sweden) was pre-stressed with different periods of pre-test swimming 24 hrs. before swimming try. The pre-test swimming periods were of duration of 0, 2.5 or 5 min. Because the pre-test swimming could not induce any additional desperation behavior in the Bal / c class (Bomhol tgard, Denmark), these mice were tested without swimming pre-test. In experiments with NMR1 mice, s.c. 15 min. before the time of forced swimming pre-test. In experiments with Balb / c mice, s.c. 15 min. before the time of swimming active test. The results are shown in Table 2. Table 2 Protective effect of dexmedetomidine (DMD) or diazepam on behavioral despair in NMR1 and Balb / c mice. T ee of na ta c y on a c t io n (± SEM; s two) d spu s of forced na tio n s of pre ct io ns pre-test Cl a s e 0 mi r. 2 . 5 min 5 mi n.

NMRl Control 44 ± 7.9 2.2 ± 2.0 1.2 ± 1.1 2. 5 μg / kg of DMD 36 ± 8.3 7.9 ± 3.9 6.8 ± 5.1 μg / kg of DMD 29 ± 5.6 1.7 ± 1.8 9.4 ± 5.1 μg / kg of DMD 36 ± 6.7 8.1 ± 3.4 3.5 ± 1.7 2 mg / kg of diazepam 42 ± 9.5 19 ± 9.8 15 ± 7.3 Balb / c Control 0.43 ± 0.23 2.5 μg / kg of DMD 0.36 ± 0.30 5 μg / kg of DMD 1.7 ± 0.72 10 μg / kg of DMD 4.9 ± 2.3 1 mg / kg of diazepam 6.7 ± 2.4 The action of the alpha-antagonist 2C-adrenoceptor MK-912, in comparison with antagonist of fa-2 -adrenoceptor non-selective RX821002, was studied using the mouse class C57BL / 6J, in a dose (15 nmol / kg sc), the dose that is different between pharmacological responses mediated by alpha-2A and fa-2C-adrenoceptor in vi vo (see above). Surprisingly, we found that the selective alpha-2C-adrenoceptor antagonist but not the nonselective fa-2 -adrenoceptor antagonist prevented the propagation of stress-induced behavioral desperation (results shown in Figure 2) in a manner similar to that observed with dexmedetomidine and diazepam (Table 2). Figure 2 shows the action of pretreatment with the alpha-2C-adrenoceptor antagonist MK-912, 15 nmol / kg (filled bar) or the fa-2 -adrenoceptor antagonist RX821002 non-selective for al-a-2 C - Adrenoceptor, 15 nmol / kg sc (striped bar) in desperate behavior induced by forced swimming stress in mice. C57BL / 6J mice were pre-treated with MK-912 or RX821002 and the active swimming time was monitored as previously described. Experiment 3 Action of the drug in anxiety in rats Another conventional test to measure the action of the drug in anxiety is a plus-maze test. In this test, a rat is placed in the middle part of the plus-maze with two open arms and two closed arms (with side walls). The rats, typically rodents, try to avoid exploring the open arms and prefer closed arms. Anxiolytic agents, such as diazepam and medetomidine (another fa-2-adrenoceptor agonist) increase the exploratory behavior and time spent in the open-arm area (Table 3), according to what has been described. in the literature of these classes of therapeutic agents (9). Typical fa-2 -adrenoceptor antagonists, such as yohimbine and atipamezole, do not increase the exploratory behavior of the rats in the elevated plus-maze test (Table 3). The test was carried out as follows: the plus - labyrinth was made of wood and consists of two open arms (45 x 10 cm), two closed arms (45 x 10 x 40 cm) with an open cover and a central square ( 10 x 10 cm). The labyrinth was raised 55 cm above the floor. Both open arms were divided into three sectors of equal size. On the day of the experiment, the rats were brought in their cage to the experiment room and allowed to adapt to their surroundings for at least one hour. The experiment room lit up normally and remained silent. Eight rats (16 in the control group) were assigned to each dose of drugs administered s.c. (or its control solution, Intralipid for diazepam and distilled water for others). The sequence of different doses was randomized using the technique to Cuadrado Latina, the experimenter continued refusing to notice the doses used. After 20 min. the rat was placed back in its box, but after 20 min. the rat was placed in the central square of the plus-maze in such a way that the rat is in front of the closed arm. The behavior of the rat was observed for 10 min. and the number of crossed sectors in the open arms and the accumulated time spent in the open arms was recorded. The results are shown in Table 3. The data are ± SEM averages. Table 3 Action of diazepam, medetomidine, yohimbine and atipamezole in the plus test - elevated labyrinth in rats. Brazos Ti emp >Treatmentor open to gas in 1 cross line the open arms Control 0 .30 ± 0.30 5. 1 ± 1.7 1 mg / kg of diazepam 7 .9 ± 1 .5 70 ± 15 3 μg / kg of medetomidine 3 .4 ± 1 .9 34 ± 10 10 μg / kg of medetomidine 4 .1 ± 2 .4 46 ± 16 0.1 mg / kg yohimbine 0.30 ± 0.30 17 ± 7.6 0.3 mg / kg yohimbine 0.80 ± 0.50 13 ± 6.2 1 mg / kg yohimbine 0.50 ± 0.50 10 ± 50 3 mg / kg yohimbine 0.30 ± 0.30 2. 4 ± 1.6 0. 03 mg / kg atipamezole 0 .90 ± 0.50 11 ± 5.4 0.01 mg / kg atipamezole 0 .50 ± 0.50 7. 6 ± 6.2 0. 3 mg / kg atipamezole 0.50 ± 0.50 1. 9 ± 1.9 Using the selective dose of alpha-2C-adrenoceptor of MK-912, this drug had a response similar to that of other anxiolytic agents. On the other hand, similar to other typical non-selective α-2-adrenoceptor antagonists, RK82100N (nmol / kg sc) did not provide any anxiolytic response, as it did not affect the exploratory behavior or the time spent in the open arms in plus elevated labyrinth (Figures 3A and 3B). Figures 3A and 3B show the pre-treatment action with 15 nmol / kg s.c. of MK-912 (filled bar) or 15 nmol / kg s.c. of RX821002 (striped bar) in the exploratory behavior in rats in a plus test - elevated maze carried out as described above. Arithmetic average values are given. Figure 3A shows the number of crossed lines in the open arm and Figure 3B shows the time spent in the open arm. Experiment 4 Action of the drug in the exploratory behavior induced by neophobic stress in rats A ladder box test is also used to study the exploratory behavior induced by neophobic stress in rodents (10). The rats, as described above, are neophobic and cautiously approach unknown territory. In a ladder box test, a rat is placed in a box containing steps. In this test, anxiolytic agents (such as diazepam and medetomidine) reduce neophobic stress and rats give more steps in the steps (Table 4), indicating an increased exploratory behavior. The therapeutic dose ranges of diazepam and medetomidine are typically very narrow because they avidly impair motor functions and vigilance, which is also clinically obvious. In this test, antagonists of alpha-2-adrenoceptor non-selective subtype such as yohimbine and atipamezole potentiate is neophobic stress in animals and fewer steps are taken. In contrast to those antagonists of the fa-2 -adrenoceptor non-selective subtype and that of RX821002, the antagonist of fa-2C -adrenoceptor MK-912 (in the selective dose of subtype 15 nmol / kg sc) does not potentiate the neophobic tension but the exploratory behavior increases as does the anxiolytics (Table 4). The experiment was carried out as follows: The apparatus consisted of a closed wooden staircase as described (10). It was composed of five identical stages of 5 cm high, 20 cm wide and 15 cm deep. The internal height of the walls (25 cm) was constant along the total length of the stairwell. On the day of the experiment, the rats were brought inside their boxes to the experiment room and allowed to adapt to their surroundings for one hour. The experiment room lit up normally and remained silent. The drugs and control solutions were injected 20 min. Before the test. After the injection the rats were put back in their boxes. Eight rats were assigned to each dose. The drugs were tested on different days and each time they had a new control group (their own). The test solutions were kept in coded bottles, in such a way that the researcher refused to notice the doses. The sequence of different doses was randomized by Cuadrado Latino. At the beginning of the test the rat was placed on the floor of the apparatus with its back to the stairs and the number of steps was recorded (steps down were not counted) for 3 min. One step was counted when the rat climbed the step completely, placing all four legs on the step. The results are given in Table 4. Table 4 Action of diazepam, medetomidine, yohimbine, antipaminol, RX821002 and MK-912 in the rat box test. Tra tami en to Sub stances (control%) Control (100) 0.3 mg / kg diazepam 111 1 mg / kg diazepam 143 3 mg / kg diazepam 71 3 μg / kg medetomidine 131 10 μg / kg of medetomidine 160 30 μg / kg of medetomidine 55 0.3 mg / kg of yohimbine 79 1 mg / kg of yohimbine 83 3 mg / kg of yohimbine 33 0.03 mg / kg of atipamezole 54 0.1 mg / kg of atipamezole 42 0.3 mg / kg of atipamezola 25 15 nmol / kg of RX821002 49 15 nmol / kg of MK-912 112 Experiment 5 Propagation of a behavioral despair state in transgenic mice A fourth piece of evidence supporting the notion of fa-2C-adrenoceptor blockade in provide protection against anxiety induced by stress and mental despair comes from experiments with transgenic mice with genetic manipulations in alpha-2C-adrenoceptor expression (11). Using the directed disruption, a mutation of the gene encoding the fa-2C-adrenoceptor was made, generating a mouse super class of al-fa-2C-adrenoceptor (alpha-2C-K0 mice). Using a pronuclear injection technique, an overexpression of the gene encoding the fa-2C-adrenoceptor was made, generating a mouse class overexpressing alpha-2C-adrenoceptor (alpha-2C-OE mice). The alpha-2C-KO and alpha-2C-OE mice were tested for their characteristics in desperation stress-induced behavior in the swimming test described in Experiment 2. According to the experiments derived from the drug described above, the alterations Genetic interactions in the expression of alpha-2C-adrenoceptor were reflected respectively in the desperation propagation of stress-induced behavior (Figures 4A and 4B). Figures 4A and 4B show the effect of altering the function of the fa-2 C-adrenoceptor on the level of expression of the gene. The transgenic mice overexpressing the alpha-2C-adrenoceptor (Figure 4A, dashed bar) were predisposed to stress-induced propagation of desperate behavior compared to their wild-type genetic controls (Figure 4A, open bar). On the other hand, the transgenic mice without expression of fa-2C-adrenoceptor (Figure 4B, dashed bar) were protected against the desperation of stress-induced behavior, compared to their control group (Figure 4B, open bar). It will be appreciated that the methods of the present invention may be incorporated in the form of a variety of embodiments, only a few of which are described herein. It will be apparent to specialists in the field that other modalities exist and do not depart from the spirit of the invention. In this way, the modalities described are illustrative and should not be construed as restrictive. REFERENCES Charney, D.S., G. R. Heninger, and A. Breier, Noradrenergic Function in Panic Anxiety. Effects of Yohimbine in Patients and Healthy Subjects with Agoraphobia and Panic Disorder (1984) Arch Gen Psych, 41, 751-763; Charney, D.S., A. Breier, P. I. Jatlow and G.R. 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Claims (8)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and therefore the property described in the following claims is claimed as property. A method for treating a mammal suffering from mental illness induced by the propagation of stress, the method comprising the step of removing or decreasing the tone of the endogenous alpha-2C-adrenoceptors in the central nervous system of the mammal. The method according to claim 1, characterized in that the mental illness is clinically expressed as a disorder selected from the group consisting of anxiety, stress, post-traumatic stress disorder, affective depression, anhedonin, allopathy, avolition, aggression or abnormality of Cognitive function initiated by neuronal degeneration induced by stress. 3. The method according to claim 1, characterized in that it comprises the administration to a mammal suffering from mental illness induced by the propagation of stress, of a therapeutically effective amount of an alpha-2-adrenoceptor antagonist or a derivative thereof, selective antagonist for the alpha-2C-adrenoceptor subtype. 4. The method according to claim 3, characterized in that administration of the fa-2-adrenoceptor antagonist selective for alpha-2C-adrenoceptor is combined with the administration of a second therapeutically active compound or a derivative thereof, wherein the The second compound is an anxiolytic, antidepressant or antipsychotic compound. The method according to claim 4, characterized in that the alpha-2-adrenoceptor antagonist selective for the fa-2C-adrenoceptor and the second compound are administered during the same treatment period. The method according to claim 5, characterized in that the selective alpha-2-adrenoceptor antagonist for the fa-2C-adrenoceptor and the second compound are administered simultaneously, optionally from a common dosage form. 7. A pharmaceutical composition useful for the treatment of mental illness induced by the propagation of stress in a mammal, the composition comprising a therapeutically effective amount of a fa-2-adrenoceptor antagonist or a derivative thereof, the antagonist being selective for al-fa-2 C-adrenoceptor, in combination with a pharmaceutically acceptable excipient. The composition according to claim 7, characterized in that the composition further comprises a therapeutically effective amount of a second compound or a derivative thereof, wherein the second compound, which does not need to be a selective antagonist for the fa- 2 C -adrenoceptor, is an anxiolytic, antidepressant or antipsychotic compound.