Mirtazapine and venlafaxine compositions with antidepressant effects and which do not alter sexual behavior

Abstract

The invention describes pharmaceutical compositions comprising mirtazapine (MTZ) and venlafaxine (VLF) which exhibit an effective antidepressant effect and at the same time do not alter normal sexual behavior. The administration of the compositions of the invention in animal models, was effective in generating an antidepressant effect without altering the normal sexual behavior of males, while in female rats it did not modify their normal estrous cycle. Likewise, the compositions of the invention further comprise the combination of low doses of mirtazapine and venlafaxine, which allows them to be a promising therapeutic option for patients with depression, since they do not produce adverse effects on sexual behavior.

Description

[0001] Mirtazapine and venlafaxine compositions with antidepressant effects and which do not alter sexual behavior

[0002] Field of the invention.

[0003] The present invention relates to the design of pharmaceutical solutions for the effective treatment of depression, particularly to pharmaceutical compositions which are useful for the treatment of depression without generating adverse effects, such as significant affectations in the sexual behavior of the patients. More particularly, the present invention comprises pharmaceutical compositions of mirtazapine and venlafaxine in certain concentrations which permit the treatment of depression and which at the same time do not generate affectations in sexual behavior.

[0004] Background of the invention.

[0005] Depression is a common and serious psychiatric disorder that affects approximately 2.8 million people worldwide (1). One of the worst consequences of depression is suicide, which causes 700,000 deaths per year. There are many options for its pharmacological treatment, however more than half of patients do not achieve remission of their depressive symptoms after treatment with a single antidepressant (2) and even if patients show an adequate response, they may have residual symptoms, such as anxiety or insomnia (3,4). Unfortunately, these residual symptoms can lead to a relapse of depression. Combining antidepressants from different pharmacological classes has been suggested as a strategy to improve treatment response. An example is the combination of mirtazapine, a noradrenergic and serotonergic specific agent (NaSSA), and venlafaxine which is a selective noradrenaline reuptake inhibitor (SNRI). Some studies have reported the high efficacy of these combined antidepressants at therapeutic doses from the beginning of treatment (5), or by the addition of mirtazapine when monotherapy with venlafaxine shows a poor response (6-9). As mentioned, such actions occur after treatment with optimal doses of mirtazapine plus venlafaxine combined, and no clinical studies have explored whether the combination using lower doses may also be therapeutically useful. In addition, gender-related differences in antidepressant response have previously been described (10-12); for example, women have a greater antidepressant response to selective serotonin reuptake inhibitors (SSRIs) (13-14) than to noradrenaline reuptake inhibitors (NRIs), whereas men respond well to both SSRIs and NRIs (12), but also to tricyclic antidepressants (11 ,14).

[0006] Several animal models are currently used for the study of depression, however, only a few meet the three main criteria for validity: face, predictive, and construct validity (15). One of these models is chronic mild stress (CMS) in which animals are exposed to different mild stressors over a period of a few weeks. In this model, the reduction of the reinforcing properties of natural stimuli such as sex or sweetness is analyzed; that is, the model mimics one of the central symptoms of depression, anhedonia (16). In addition, CMS produces a wide variety of somatic, physiological, biochemical, neurobiological, and behavioral alterations that are comparable to those exhibited by depressed patients (17-19), and many of these changes are reversed after chronic (but not acute) treatment with antidepressants (20). The main disadvantage of CMS is the long time and effort required to obtain results (21). The antidepressant effect of mirtazapine on CMS has been evaluated previously; Barbar et al (22) reported an increased sucrose preference in male rats with CMS-induced anhedonia following administration of 10mg / kg mirtazapine, while Zhang et al (23) reported an antidepressantlike effect with administration of 5 mg / kg mirtazapine for six weeks in male rats subjected to CMS. The latter study also reported a similar effect with the administration of venlafaxine (30 mg / kg) for the same period. Likewise, administration of 10 mg / kg venlafaxine for 21 days has been shown to produce an antidepressant-like effect in male and female rats subjected to stress (24). On the other hand, the forced swimming test (FST) is a widely used, quick and easy to perform method to evaluate depressive behavior and the efficacy of some treatments. This test is based on the behaviors shown by the animal in an unavoidable situation: forced swimming. Initially, the animal displays active behaviors such as swimming, diving or climbing, but eventually adopts a posture of immobility, which is considered to reflect behavioral despair (25). Although immobility in the FST has recently been considered an adaptive behavior rather than a valid measure of depression and despair (26), this test has a high sensitivity to a wide range of antidepressants and is useful as a screening method to identify the antidepressant properties of new drugs (27). Using this test, the antidepressant effect of mirtazapine, at doses ranging from 10 to 40 mg / kg, has been confirmed in several studies (22,28-30). In a previous study, 40 mg / kg was the effective dose of mirtazapine on FST in male and female rats (31), however, this dose caused significant sedation, probably because it antagonizes H1-histaminergic receptors (32). Venlafaxine, on the other hand, was effective in reducing immobility in FST at 60 mg / kg in male and female rats (31), whereas in other studies its antidepressant effect was observed in a dose range of 10-80 mg / kg (33-34). The effects of the mirtazapine-venlafaxine combination in female rats on FST have been reported previously (30), where it has been shown that a combination of low doses of mirtazapine and venlafaxine, administered in a subchronic schedule to hormonally primed ovarectomized rats, produced a reduction in immobility counts, with an increase in swimming behavior. Despite the above, one of the main side effects of antidepressants, administered either alone or in combination, are related to sexual behavior. Antidepressants in general produce a wide range of sexual side effects that are related to their target neurotransmitter systems. For example, many studies have shown that antidepressants acting on the serotonergic system decrease male (35) and female (36-37) sexual behavior, whereas antidepressants acting on catecholaminergic systems (e.g., bupropion) have the opposite effect (35,38). In humans, the estimated incidence of antidepressant- related sexual dysfunction is close to 40%, although the exact figure is unknown (39). In men, the most frequent sexual side effects of antidepressants are erectile and ejaculatory difficulties (40), whereas in women the main effects are related to sexual desire, arousal and orgasm (41). These side effects have an impact on patients' quality of life and can lead to treatment withdrawal. Antidepressant drugs that consistently produce sexual dysfunction are those with serotonergic effects, such as selective serotonin reuptake inhibitors (SSRIs), fluoxetine or sertraline, and serotonin-norepinephrine reuptake inhibitors (SNRIs) with higher affinity for the 5-HT transporter, duloxetine or venlafaxine (42- 44). Other antidepressants, such as tricyclics, also produce sexual side effects in a variable proportion, depending on the neurotransmitter system that is predominantly modified, since these drugs have affinity for a wide range of receptors and transporters (44-45). Finally, the lowest incidence of sexual dysfunction has been observed with some drugs that block 5-HT2 receptors, such as mirtazapine and nefazodone, and the norepinephrine-dopamine reuptake inhibitor (NADRI), bupropion (39).

[0007] Previous studies in rats have shown that a subchronic administration of the combination of mirtazapine and venlafaxine with antidepressant effect did not alter the proceptivity and receptivity of ovariectomized female rats, however it is unknown whether chronic treatment of the combination of mirtazapine plus venlafaxine, as used in clinical practice, produces any effect in animal models to study depression and whether it affects the manifestation of male and female sexual behavior in animals without any manipulation. On the other hand, patents JP2013032308, WO201202083493, NZ573570, CN101987198 and RU2007140986 describe compositions comprising various active ingredients in combination or not with mirtazapine and venlafaxine for the treatment of depression or anxiety disorders; however, none of them describe that such compositions do not generate adverse effects on sexual behavior as a result of the treatment.

[0008] Therefore, it is important to have better solutions for the treatment of depression and at the same time not to observe adverse effects on the sexual behavior of patients as a result of such therapeutic treatment.

[0009] Summary of invention.

[0010] Depression is a common psychiatric illness affecting millions of people worldwide. Pharmacological approaches to treat depression are not always effective and produce side effects, the severity of which is related to the neurotransmitter system affected by the antidepressant. One such side effect is male and female sexual dysfunction, which often goes undiagnosed, but can lead to treatment withdrawal. In accordance with the present invention, one approach to solving this problem is the use of two antidepressants in combination, for example, mirtazapine (MTZ) and venlafaxine (VLF), wherein the combination of these antidepressants has been shown to be effective in treating unipolar and treatment-resistant major depression in humans. As described here, in ovariectomized female rats, the combination of mirtazapine and venlafaxine in a subchronic scheme, produced an antidepressantlike effect in the forced swimming test (FST), without modifying sexual behavior. To achieve the above effect, we analyzed whether chronic administration of a low-dose combination of mirtazapine and venlafaxine produced antidepressant-like effects and affected sexual behavior in gonadally intact male and female rats, using young adult male and female rats. Intact male and female rats were used to evaluate the effect of a 14-day administration of MTZ and VLF 2.5 / 3.75 mg / kg and 5 / 7.5 mg / kg combinations or their vehicles on FST. Independent groups of animals were used to evaluate the effect of the MTZ / VLF 5 / 7.5 mg / kg combination or their vehicles for 21 days on anhedonia induced by the chronic mild stress protocol (CMS). For the evaluation of sexual behavior, males were trained for sexual experience, while females were not manipulated except for daily vaginal swabs. Rats were injected with the combination of MTZ / VLF 5 / 7.5 mg / kg, or their vehicles for 21 days (males), or 21-24 days (females). In accordance with the invention, administration of the combination of MTZ and VLF 2.5 / 3.75 did not produce an antidepressant-like effect, while the 5 / 7.5 mg / Kg combination of the invention was effective in reducing immobility in the FST. In CMS, administration of MTZ / VLF (5 / 7.5 mg / kg) reversed anhedonia in male and female rats. Furthermore, this antidepressant-effective combination of the invention did not alter male sexual behavior, while in female rats, the MTZ / VLF 5 / 7.5 mg / Kg composition of the invention did not modify the estrous cycle, nor the display of proceptive and receptive behaviors. As can be seen, the compositions of the invention comprising the combination of low doses of mirtazapine and venlafaxine are a promising therapeutic option for patients with depression, since they do not produce adverse effects on sexual behavior.

[0011] Brief description of the figures.

[0012] Figure 1. Immobility (a,c), swimming and climbing (b,d) counts obtained from male and female rats administered with two different combinations of mirtazapine and venlafaxine (2.5 / 3.75 and 5 / 7.5 mg / kg, respectively), or their vehicles for 14 days and subjected to FST are shown. One-way ANOVA, Dunnett post hoc; *p<0.05; **p<0.01 , *** p<0.001 vs. vehicle, n=8 per group.

[0013] Figure 2. Water and sucrose solution intake of male rats exposed (a) and unexposed (b) to CMS before and during treatment with the combination of mirtazapine and venlafaxine 5 / 7.5 mg / kg, or their vehicles for three weeks is shown. Repeated measures two-way ANOVA, post hoc Tukey, ***p<0.001 sucrose + treatment vs sucrose + vehicle, n=8 per group.

[0014] Figure 3. Water and sucrose solution intake of female rats exposed (a) and not exposed (b) to CMS before and during treatment with the combination of mirtazapine and venlafaxine 5 / 7.5 mg / kg, or their vehicles for three weeks is shown. Repeated measures two-way ANOVA, post hoc Tukey, *p<0.05; ***p<0.001 sucrose + treatment vs sucrose + vehicle, n=8 per group.

[0015] Figure 4. Shown are the number of ejaculations in 30 min (a), intromission latencies of the first ejaculatory series (b), number of mounts (c), intromissions (d) and ejaculation latencies of the first two ejaculatory series of sexually experienced male rats treated with the combination of mirtazapine and venlafaxine 5 / 7.5 mg / kg, or vehicle for 21 days. Mann-Whitney U test, *p<0.05; **p<0.01 vs. vehicle, n=8 per group.

[0016] Figure 5. The number of different phases of the estrous cycle (a), and number of jumps, darts and ear wiggles (b), lordosis quotient (c) and lordosis intensity (d) shown for female rats treated with the combination of mirtazapine and venlafaxine 5 / 7.5 mg / kg, or vehicle, for 21-24 days. Mann-Whitney U test, ns, n=8 per group.

[0017] Detailed description of the invention.

[0018] The present invention provides pharmaceutical compositions comprising low doses of mirtazapine (MTZ) and venlafaxine (VLF) for the effective treatment of depression without causing adverse effects on the sexual behavior of treated patients; particularly the compositions described herein comprise a combination of MTZ and VLF of 5 / 7. 5 mg / kg correspondingly, which were found to be effective for the treatment of depression under a chronic (14-day) administration schedule and without causing the adverse effect of sexual behavioral impairment that has been observed with other combinations of such drugs. In contrast, different combinations of MTZ and VLF such as for example 2.5 / 3.75 mg / Kg correspondingly, did not produce an antidepressant effect.

[0019] In accordance with the present invention, the results described herein show that the combined treatment with mirtazapine and venlafaxine (5 and 7.5 mg / Kg, respectively) produces an antidepressant-like effect in the forced swimming test and in the chronic mild stress model, while at the same time lacking action on male or female sexual behavior.

[0020] Therefore, it is one of the objectives of the invention to provide pharmaceutical compositions comprising mirtazapine and venlafaxine together with pharmaceutically acceptable excipients suitable to be administered to the patient requiring it. It is modality of the invention to adapt the active principles for use in pharmaceutical compositions for enteral administration, parenteral and topical use, including inhalation. The effective patient doses of the active principle will also be adjusted in accordance with preclinical and clinical studies, but taking as a basis the findings of the present invention.

[0021] Examples of pharmaceutically acceptable excipients accompanying the active principle of the invention are for example, for oral administration as tablets or tablets, agents comprising for example, diluents, binders, stabilizers, bulking agents, thickening agents, such as povidone, microcrystalline cellulose, lactose, etc., disintegrating agents such as for example cross-linked carboxymethyl cellulose, surfactants such as for example sodium lauryl sulfate, lubricating or sliding agents such as for example magnesium stearate, colloidal silicon dioxide, etc., wherein said excipients may be formulated for preferably slow or prolonged release for a systemic effect.

[0022] Solutions for intravenous or intraperitoneal administration of the active principle can be prepared by first dissolving them in an organic solvent such as DMSO, ethanol, or dimethylformamide and subsequently in aqueous buffers, such as PBS.

[0023] Particular preference is given to dosage forms designed for systemic administration, wherein liquid or solid compositions can be formulated, suitable for administration and whose excipients can be selected for example from components compatible with said dosage form, for example of lipidic or peptidic nature, or peptidomimetics, known in the prior art as non-immunogenic, and which preferably can be bound to the active principles of the invention to improve their bioavailability; propellant agents such as, for example, propane, butane, or permissible chlorofluorocarbons; pH regulators such as, for example, sulfuric acid; chelating agents such as, for example, EDTA. The active ingredients can also be formed into micronized particles contained in gelatin capsules or other systems known in the technical field, which assist in releasing the active ingredient to its target site of action, for example, by means of solid dosage forms such as tablets or dragees, including those formulated for prolonged release.

[0024] According to the present invention, the synergistic compositions described herein may be obtained by combining mirtazapine and venlafaxine with pharmaceutically compatible vehicles known in the art, in the amounts and / or concentrations corresponding as described herein, and compounds known in the art may be included to obtain such compositions. Likewise, the administration of such compositions, may be made depending on the conditions of the patient, which will determine the doses and frequency of administration necessary to achieve an effective treatment of the ailment each particular case, although it is preferred to dose the synergistic compositions of the invention in a chronic manner with the purpose of providing the patient with an effective treatment against depression and which at the same time does not generate adverse effects on his sexual behavior.

[0025] In another embodiment of the invention, methods of treatment for patients with depression are included, comprising administering to the patient with said condition the pharmaceutical compositions of the invention, in the amounts, dosage frequency and treatment time indicated by the treating physician and based on the results obtained in the present invention. As can be seen from the results described herein below, said compositions will have an effective therapeutic effect for the treatment of depression in patients affected by said condition and at the same time will not generate adverse effects on their sexual behavior.

[0026] The antidepressant effect of the compositions of the invention comprising a mirtazapine / venlafaxine combination and which was observed in FST, was previously described in ovariectomized (steroid- primed) female rats with the same doses used in the present invention, but in a subchronic administration schedule of three administrations (30). These data indicate similarly to previous reports (29), that subchronic treatments are as effective as chronic treatments in producing similar actions. Furthermore, lower doses of this antidepressant combination, even chronically administered, failed to produce antidepressant action. In the present invention, we demonstrated that the antidepressant combination of mirtazapine and venlafaxine at 5 and 7.5 mg / kg administered chronically for 14 days was equally effective in gonadally intact male and female rats. It is worth mentioning that in this experiment, as well as in the one using CMS, the estrous cycle of females was not considered because exposure to these stressors alters its regularity (46-47).

[0027] Antidepressant effect of mirtazapine plus venlafaxine.

[0028] FST. As mentioned above, the individual effects of mirtazapine or venlafaxine have been evaluated before; however, the antidepressant effect of the combination of mirtazapine plus venlafaxine had not been extensively studied until prior to the present invention. Notably, when such drugs were combined, much lower doses of each antidepressant were required to produce an antidepressant-like effect. A previous analysis (30) showed that the minimum effective doses in combination were one-eighth of the doses required administered individually to achieve the same effect in both male and female rats. Currently, when a combination of mirtazapine and venlafaxine is prescribed, the doses used are the same as when administered individually, which could produce more adverse effects, so the results shown in the present invention could serve as a basis for obtaining an effective pharmaceutical combination of mirtazapine and venlafaxine with therapeutic effects for the treatment of depression, but without adversely affecting other aspects.

[0029] In all evaluations, the effective dose combination used in the compositions of the invention was 5 / 7.5 mg / kg. This was based on previous experiments in which higher dose combinations (10 / 15 and 20 / 30 mg / Kg) were evaluated; although these combinations showed a similar effect to the antidepressant, they produced intense side effects, such as sedation and severely altered motor activity (30), which could severely modify the outcome of the experiments. Although the effective combination of mirtazapine and venlafaxine (5 / 7.5 mg / kg) of the invention also produced a reduction in spontaneous activity, the treated rats showed less immobility in the FST, so the effect of the drug combination is considered to be antidepressant-like (27).

[0030] Regarding sex comparisons in FST, the combination of mirtazapine and venlafaxine of the present invention exerted a similar antidepressant effect in males and females, where the main difference was that in males, the antidepressant combination increased swimming and climbing behaviors, whereas in females it only increased swimming behavior. This sex differential increase in active behaviors was also observed after combined administration of mirtazapine and venlafaxine in a subchronic program in ovarectomized and steroid-primed males and females. This effect seems to be due to the fact that estrogens favor the actions of mirtazapine and venlafaxine on the serotonergic system, which is involved in an important way in the modulation of swimming behavior (31).

[0031] Chronic mild stress. In this study, chronic treatment with mirtazapine plus venlafaxine 5 / 7.5 mg / kg reversed anhedonia in both sexes. In addition to the behavioral change evaluated here (reduction in sucrose consumption), rats exposed to CMS have been observed to show a reduction in brain levels of serotonin, noradrenaline and dopamine that is reversed by antidepressants such as fluoxetine (48); this effect on neurotransmitters can also be achieved with the combination of mirtazapine plus venlafaxine, since these antidepressants exert a synergistic action on the serotonergic, noradrenergic and dopaminergic systems (49). In addition, chronic treatment with mirtazapine (16 mg / kg) in rats reverses anhedonia and reverses the reduction of GABA and the increase in glutamate levels in the nucleus accumbens produced by CMS (50). In another study, 5 mg / kg mirtazapine increased brain levels of BDNF in male rats after CMS (23). These changes in GABA, glutamate and BDNF are also observed in patients with depression, and their reversal plays an important role in the improvement of depressed mood (51-53). Venlafaxine (30 mg / kg) in rats exposed to CMS also reversed anhedonia and produced an increase in BDNF (23). Chronic venlafaxine (5 and 10 mg / kg) also reduced the expression of SWOB protein, which is a marker of glial activity that has been found to be increased in depressed patients (54). Another effect of CMS in rats is hyperactivity of the hypothalamic-pituitary- adrenal (HPA) axis, which also plays an important role in the pathogenesis of human depression (55- 56), and impaired glucocorticoid feedback inhibition, leading to increased corticosterone levels (57- 58). According to Xing et al. (24), chronic administration of venlafaxine in male and female rats reduced the elevation of corticosterone levels produced by CMS exposure, an effect also observed after chronic administration of mirtazapine in males (22-23).

[0032] Consistent with the present invention, after two weeks of antidepressant treatment, the rats began to increase sucrose consumption in response to treatment. This is consistent with many studies showing a similar response pattern in rats exposed to CMS and treated with different antidepressant drugs (23,59-61) and reinforces the predictive validity of the model that refers to the fact that chronically stressed animals show a recovery of depressive-like behaviors only after chronic antidepressant treatments, similar to what occurs in humans (62-63).

[0033] In accordance with the invention, the comparison between sexes in the CMS yielded interesting results. First, male rats did not respond to the CMS programming used in females, so some stressors had to be modified to induce anhedonia in males. These data are consistent with previous studies reporting that young adult male rats are less susceptible to stress-induced anhedonia than either males or older females (24,46,64-66). Male rats are more susceptible to acute stress but show rapid adaptation to chronic stress (67); the greater vulnerability of female rats to chronic stress appears to be related to estrogens, as they stimulate corticotropin-releasing hormone synthesis in the hypothalamus. Estrogens also impair the negative feedback of corticosterone, thereby potentiating the HPA axis dysfunction induced by chronic stress (24). Second, treatment with the combination of mirtazapine and venlafaxine produced a similar final effect after 3 weeks, but the onset of action in female rats appears delayed compared with male rats. Finally, it is important to note that the fluid intake of the non-stressed groups of animals remained stable throughout the study, even during administration of the mirtazapine plus venlafaxine combination. These results suggest that the antidepressant combination of the invention did not cause increased fluid intake in the stressed groups, i.e. , it did not have a dipsogenic effect, but reversed the anhedonia produced by CMS.

[0034] Effect of mirtazapine plus venlafaxine on sexual behavior.

[0035] Males. In male rats, chronic administration of the combination of mirtazapine plus venlafaxine of the invention increased the number of intromissions required to ejaculate in the two successive copulatory series and reduced the latency of intromission, with no effect on the other parameters. The increase in the number of intromissions can be interpreted as a greater requirement for penile stimulation by the male to achieve ejaculation, however, ejaculation latencies in both copulatory series did not differ between groups. Calculation of the inter-intromission interval indicated a decreasing trend in antidepressant-treated males that did not reach statistical significance. Thus, males treated with the antidepressant compositions of the invention did not show an alteration of sexual performance. On the contrary, the reduction of intrusion latency suggests a facilitating effect of the combination of mirtazapine and venlafaxine of the invention on sexual motivation (68).

[0036] To our knowledge, the present invention is the first study to report on the effects of combined mirtazapine and venlafaxine on sexual behavior in male rats. However, there are reports on the consequences of chronic administration of mirtazapine or venlafaxine, administered separately, on the sexual behavior of male rats. Benelli et al (69) reported an improvement in sexual motivation, as determined by an increase in the number of crossings of an electrified grid by male rats to reach a receptive female and in the proportion of males reaching ejaculation under such conditions, after chronic administration of mirtazapine (10 mg / kg), whereas chronic administration of venlafaxine (40 mg / kg) adversely affected sexual behavior by reducing ejaculation frequency (70). These data suggest opposite effects of these antidepressants on the sexual behavior of male rats and allow us to propose that the absence of significant effects on sexual activity after their combined treatment could be the result of a balance between sexual facilitatory (mirtazapine) and inhibitory (venlafaxine) actions. In fact, there is evidence of an attenuating effect of added mirtazapine on the reduction of ejaculation frequency and inhibition of sexual motivation produced by fluoxetine in male rats (69). A similar effect has been described in humans, where the addition of mirtazapine reverses sexual dysfunction induced by SSRI treatment (71-73). This reversal of SSRI-induced sexual inhibitory effects is probably due to the 5-HT2 receptor antagonist properties of mirtazapine, since 5-HT2 receptor activation is related to the development of SSRI-induced sexual dysfunction, which is thought to be produced by a reduction in noradrenergic and dopaminergic transmission (74-75).

[0037] Females. Regarding the effect of mirtazapine or venlafaxine on the sexual behavior of female rats, there is a single report showing that, when administered individually, higher doses of each of these antidepressants reduced the sexual behavior of females. Thus, venlafaxine at a dose with an antidepressant effect (60 mg / kg) reduced the proceptive behaviors displayed by ovariectomized and hormonally primed female rats, without affecting lordosis, whereas mirtazapine, at a dose of 40 mg / kg markedly decreased both proceptivity and receptivity (30). However, low doses of mirtazapine (5.0 mg / kg) and venlafaxine (7.5 mg / kg) combined did not affect proceptivity or receptivity (30). One possible explanation for the lack of sexual effects of this combination is that the mirtazapine-mediated increase in serotonin (which reduces female sexual behavior (76-77) could be counteracted by the addition of venlafaxine, which increases the release of dopamine and noradrenaline (78). Another possibility is that the low doses of mirtazapine and venlafaxine present in the compositions of the invention are below the threshold for modifying female sexual behavior, even though they were effective in reducing depressive-type behaviors (30).

[0038] The combination of mirtazapine and venlafaxine of the present invention did not modify the regularity of the estrous cycle, which made it possible to evaluate its effect on the sexual behavior naturally expressed by female rats during late proestrus. There are several studies on the effect of antidepressants on the estrous cycle. For example, Domingues et al (79) reported irregular estrous cycles and an increase in the occurrence of the metestrous phase in female mice after chronic treatment with high doses of fluoxetine (20 mg / kg for 14 days), an effect that was not observed with lower doses (2 mg / kg), while 10 mg / kg fluoxetine, administered in a chronic schedule, did not induce changes (80) or produced only a modest effect on cyclicity (81). In women, no effects of antidepressants, regardless of their class, on menstrual cycle regularity have been reported (82).

[0039] As mentioned above, the two most relevant problems for patients receiving antidepressants are their inability to reduce depressive symptoms and their negative effects on sexual function. These caveats hinder the depressed patient's adherence to treatment, affecting his or her long-term prognosis. The results obtained in the present invention indicate that the combination of low doses of mirtazapine and venlafaxine are a promising therapeutic alternative to treat depression without producing adverse effects on sexual behavior.

[0040] Example 1. Materials and methods.

[0041] Animals. Young (180-250 g) and male (300-400 g) adult Wistar rats were used. All animals were maintained under 12 h / 12 h reversed light-dark cycle conditions, with lights on at 22:00 h, in a room with controlled temperature (21 ± 1 °C) and humidity. Animals were maintained in same-sex groups of five to six per cage, with ad libitum access to water and food (unless otherwise required).

[0042] All experimental procedures were performed in accordance with the Mexican Official Standard for the care and handling of animals (NOM-062-ZOO-1999) and were approved by the Institutional Ethics Committee of CINVESTAV-IPN and were approved by the Institutional Committee for the Care and Use of Laboratory Animals (CICUAL; protocol number 0025-13). Drugs. Mirtazapine (MTZ) was dissolved in physiological saline with 0.5% acetic acid, while venlafaxine hydrochloride (VLF) was dissolved in physiological saline. Both drugs were administered intraperitoneally following a chronic schedule (last administration 1 hour before the test) in a volume of 2 ml / kg.

[0043] Forced swim test (FST). The FST is widely used for the evaluation of antidepressant drugs. This test is based on the observation that rats, when placed in a cylinder with water and forced to swim, eventually develop behavioral despair, observed as increased immobility.

[0044] The procedure consisted of placing male and female rats in individual glass cylinders (45 cm high x 20 cm diameter) that had been filled with water to a depth of 30 cm (83). Two swimming sessions were performed: a 15-min pretest, followed 14 days later by a 5-min test. Pharmacological treatments were administered between these sessions. After both sessions, the rats were removed from the cylinders, dried with towels and placed in heated cages, and then returned to their home cages. The test sessions were videotaped for subsequent scoring of three different behaviors: immobility, swimming and climbing. The behaviors were scored after a 5-second period, so 60 counts were obtained over the 5-minute test sessions.

[0045] Mild chronic stress model (CMS). Sucrose consumption training. All rats (male and female) were allowed to adapt to the taste of a sucrose solution (1 %) for two consecutive weeks. During this period, the usual water bottle was replaced by a bottle containing sucrose solution for one hour every day at the beginning of the dark phase (10 am). At the end of this adaptation time, basal sucrose intake was determined. Prior to measurement, rats were deprived of food and water for 20 h and then presented with two bottles for 1 h: one with sucrose solution (1%) and one with water. Fluid intake (sucrose solution or water) was measured by weighing the bottles before and after the test. To determine that the rats had developed a preference for sucrose, sucrose solution intake had to be > 4 g, and at least twice the amount of water consumed. Only animals that met these criteria were included in the study. In female rats, the CMS paradigm that effectively reduced sucrose intake was: white noise (~90 dB), continuous light, crowding (2-3 animals per cage), strobe light (300 flashes / min), cage tilt 45° along the vertical axis, dirty cage (250 ml of water spilled on bedding), and water deprivation (Table 1). This scheme has been reported to induce anhedonia in young and old adult male (64) and female (84) rats. On the other hand, young adult male rats were subjected to a modified CMS schedule, since these animals did not respond to the previously mentioned stressor schedule: white noise and continuous light were replaced by ultrasonic radiation of varying intensity (20-45 kHz). Rodents emit ultrasonic vocalizations, in the range of 20-25 kHz, in response to life-threatening situations, while the emission of 25-45 kHz vocalizations represents a "neutral emotional state". Studies have shown that continuous exposure to these ultrasonic frequencies induces depressive-like behaviors in rats and mice (85-87). In addition, male rats were exposed to the protocol for a longer period (4 weeks). Control groups of unstressed animals were maintained for 3 weeks without stress, but under handling and storage conditions comparable to those of the stressed animals.

[0046] In all groups, the sucrose solution and water consumption of the rats was determined weekly after a 20-h period of food and water deprivation (TEST, Table 1). This evaluation consisted of exposure for 1 h to two bottles: one with sucrose solution and the other with water. The anhedonic state generated by CMS was reflected as a reduction in sucrose consumption of at least 2 g in two successive evaluations, or at least 5 g between baseline and final tests (64). Classification of animals as anhedonic or nonanhedonic was performed after 3 weeks (females) or 4 weeks (males) of CMS, based on their intake of sucrose solution assessed weekly.

[0047] Table 1. Chronic mild stress (CMS) scheme used to induce anhedonia in female and male rats.

[0048] WN: white noise (~ 90 dB), OC: overcrowding (2-3 rats per cage), CL: continuous light, SC: dirty cage (250 ml of water spilled on the bedding), SL: strobe light (300 flashes / min), WD: water deprivation, CT : cage tilt (45°), FD: food deprivation. Abbreviations in parentheses show stressors that were substituted for ultrasonic sound (US) in male rats.

[0049] Observations of sexual behavior.

[0050] Male sexual behavior. Male rats were subjected to sexual training sessions (3-5 times) with receptive females for sexual experience. The sessions were conducted on alternate days. Males were considered sexually experienced when they achieved ejaculation in 15 min or less in three consecutive training sessions. For evaluation of sexual behavior, male rats were introduced into the mating scenario and allowed a 5-min habituation period before introducing a sexually receptive female. Sexual interaction was allowed for a period of 30 min and videotaped for later analysis. Copulatory parameters scored for each copulatory series were latencies to first mounting or intromission, number of pre-ejaculatory mountings and intromissions, ejaculatory latency (time elapsed between first intromission and ejaculation), the interejaculatory interval (ejaculatory latency divided by the number of intromissions), the postexejaculatory interval (time elapsed from ejaculation to the appearance of the first intromission of the next series), and the number of visualized ejaculations.

[0051] Female sexual behavior. Female rats used for the evaluation of sexual behavior received no manipulation other than daily sampling of vaginal smears for 14 days prior to the start of the experiment, and until the last day of drug administration. The phases of the estrous cycle were determined according to the description of Marcondes et al (88).

[0052] Female rats selected during the late proestrus phase of the estrous cycle were placed in a cylindrical mating arena (50 cm diameter x 40 cm height). Five minutes before introducing the female rat, a sexually experienced male was placed on the stage and the animals were allowed to interact sexually until the female received 10 mounts from the male. Sexual activity was videotaped to analyze proceptive and receptive behaviors. The proceptive behaviors recorded were leaping, scurrying, and ear wiggling (for descriptions, see Erskine 89). To measure responsiveness, lordosis intensity (IL) was assessed using a four-point scale from 0 to 3 as described by Hardy & DeBold (90) and lordosis quotient (LQ) was determined using the following formula:

[0053] No. Lordosis quotient / 10 mounts x 100.

[0054] Open field test. Locomotor activity was measured individually using an actometer (Panlab LE 8825), which consisted of a polypropylene box (45 x 45 x 45 x 20 cm) with two infrared frames. The rat was placed in the center of the box and left there for five minutes, and counts of general activity, stereotyped movements, and flares were obtained. At the end of each individual test, the box was cleaned with 70% alcohol.

[0055] Effect of chronic administration of the combination of mirtazapine and venlafaxine on FST. The same doses of antidepressants were administered to male and female rats. The combinations evaluated by FST were 2.5 / 3.75 and 5 / 7.5 mg / kg of mirtazapine and venlafaxine, respectively. The doses were chosen based on previous experiments that confirmed their efficacy in reducing depressive-like behaviors in a subchronic scheme (30). Male and female rats were divided into two groups (8 animals each), one group received the combination of antidepressants and the other group, the vehicles. Daily administrations for 14 days were performed in the first 4 hours of the dark phase of the cycle.

[0056] Effect of chronic administration of a mirtazapine-venlafaxine combination in the CMS model. Male and female rats exposed to CMS were housed individually. Groups subjected to the CMS protocol were placed in an isolated room to prevent unstressed control groups from accidental exposure to stressors, and these rats were housed under standard biotherium conditions. At the end of the anhedonia induction period (three weeks in female and four weeks in male rats), the CMS-exposed and nonexposed animals were subdivided into two groups, each of which received the combination of mirtazapine and venlafaxine 5 / 7.5 mg / kg respectively, or their vehicles, for a period of 21 days, thus resulting in four subgroups per sex. During the treatment period, the rats in the CMS groups continued to be exposed to the stressors, while the control rats remained without stressors in the biotherium. All groups were tested weekly to determine the effect of the combination of antidepressants, or their vehicles, on anhedonia-like behavior.

[0057] Effect of chronic administration of a mirtazapine-venlafaxine combination on sexual behavior in male and female rats. Animals of both sexes were used and treated with the same doses of the combination of the antidepressants mirtazapine (5 mg / kg) and venlafaxine (7.5 mg / kg). The doses were chosen for their efficacy in reducing depressive-like behaviors (30). Male and female rats were divided into two groups (8 animals each), one group received the antidepressant combination and the other group, the vehicles. Daily administrations were performed during the first 4 hours of the dark phase. Male rats were treated for 21 days, while females received treatment for at least 21 , and up to 24 days, until the onset of the vaginal proestrus phase, during which their sexual behavior was recorded.

[0058] Statistical analysis. FST data are presented as means ± standard errors and were analyzed by Kruskal-Wallis ANOVA followed by Dunn's test, except for comparisons by sex, where a two-way ANOVA and Tukey's test were used. Spontaneous motor activity and CMS are presented as means ± standard errors and analyzed by Kruskal-Wallis ANOVA followed by Dunn's test (motor activity), or two-way repeated measures ANOVA followed by Tukey's test (CMS). Pairwise comparisons of two groups were performed using the Mann-Whitney U test. Sexual behavior results are presented as medians and interquartile ranges. Comparisons were calculated between control and drug-treated groups. Differences were considered statistically significant at a p-value < 0.05.

[0059] Example 2. Effect of chronic administration of the combination of mirtazapine and venlafaxine on FST in male rats. Concomitant administration of the compositions of the invention comprising mirtazapine (5 mg / kg) and venlafaxine (7.5 mg / kg) for 14 days reduced immobility counts in the FST in male rats (Kruskal-Wallis ANOVA H2 = 14. 84, p= 0.006, Dunn's p=0.0016), accompanied by a significant increase in both swimming (Dunn's p=0.009) and climbing (Dunn's p=0.05) (Figure 1 b). These doses were chosen in accordance with a previous study, which showed this combination to be effective in a subchronic administration schedule in female Wistar rats (three administrations / 24 h) (30). It is also known that chronic treatments show an antidepressant effect with lower doses of drugs, compared to those needed to observe the same effect with a subchronic scheme (91). For this reason, for the purposes of the present invention a combination of lower doses of mirtazapine and venlafaxine (2.5 / 3.75 mg / kg) was tested. However, and as described here, this combination was not effective in reducing immobility counts in male rats (Dunn's p=0.99), nor in increasing active behaviors (Dunn's, ns, for both swimming and climbing) (Figure 1a).

[0060] In female rats, the combination of mirtazapine and venlafaxine (5 / 7.5 mg / kg) for 14 days also exerted a similar effect to the antidepressant (Kruskal- Wallis ANOVA H2 = 18.56, p=0.0001 , Dunn's p=0.0004) (Figure 1c) with an increase in swimming (Dunn's p=0.0006) but not climbing (Dunn's, ns) behavior (Figure 1d). Likewise, the combination of mirtazapine and venlafaxine 2.5 / 3.75 mg / kg did not exert an antidepressant effect in females (Dunn's p= 0.99).

[0061] To compare whether the antidepressant effect of the combination of mirtazapine and venlafaxine differs in immobility behavior between males and females, a two-way ANOVA was performed, taking sex and treatments as factors. In immobility, the results showed a significant effect for sex and treatment, but not in their interaction (Sex: F1 ,39 =41.04, p<0.0001 ; Treatments F2,39 =48.38, p<0.0001 ; Interaction: F2,39 =0.5686, p=0.57). This sex difference is due to the different basal levels of immobility shown by males (43 counts / 5 minutes) and females (31 counts / 5 minutes). The combination of mirtazapine plus venlafaxine produced the significant treatment effect. However, the lack of interaction indicates a similar antidepressant effect in males and females. Comparison of active behaviors between sexes showed a difference in climbing behavior in sex and treatment factors, with no interaction (Sex: F1 ,39 =9.2, p=004; Treatments F2,39 =3.69, p=0.03; Interaction: F2,39 =1. 7, p=0.19, ns); while in swimming behavior, a difference was only found in the treatment factor (Sex: F1 ,39 =2.55, p=0.11 ; Treatments F2,39 =26.31 , p<0.0001 ; Interaction: F2,39 =1.02, p=0.36). Such differences were due to the increased swimming and climbing observed only in males after this combination (vide supra).

[0062] Spontaneous motor activity was measured to determine whether the combinations of mirtazapine and venlafaxine used in FST produced motor disturbances. Table 2 shows the number of exploratory movements shown by male rats treated with two combinations of mirtazapine and venlafaxine, or vehicles. No statistical differences were found between the 2.5 / 3.75 combination and the control group; however, the higher dose combination (5 / 7.5) did reduce the spontaneous activity of the rats (Kruskal-Wallis ANOVA, H2 = 14.15, p=0.008; Dunn's p=0.003).

[0063] Table 2. Number of exploratory movements shown by male rats after administration of two combinations of mirtazapine and venlafaxine (2.5 / 3.75 and 5 / 7.5 mg / kg), or vehicles. Kruskal-

[0064] Wallis ANOVA, post hoc Dunn's, ** p<0.01, n=8 per group.

[0065] Example 3. Effect of chronic administration of the combination of mirtazapine and venlafaxine in the CMS model in male rats. Of the initial group of 25 male rats, 24 (96%) showed a clear preference for sucrose over water. These animals were then exposed to the CMS protocol for three weeks. At the end of this time, all animals had reduced their sucrose intake; however, this reduction was not sufficient to meet the above criteria. Therefore, the animals were exposed to CMS for an additional week. At the end of this time, 16 rats met the criteria for anhedonia, and began treatment with the combination of mirtazapine and venlafaxine 5 / 7.5 mg / kg, or their vehicles. After the first week of treatment, no differences were found between the groups. However, at the end of the second week of treatment, a significant increase in sucrose intake was observed in the antidepressant-treated group, and this increase persisted until the third week of treatment (2 -way RM ANOVA: time: F7,196 = 22. 36, p<0.0001 ; treatment: F3,28 = 71.28, p<0.0001 ; interaction: F21 ,196 =9.41 , p<0.0001 ; p=ns at week 1 ; p<0.001 at weeks 2 and 3 after treatment vs. vehicle stressed controls) (Figure 2a) (Figure 2a). Likewise, when comparing sucrose intake in males after the third week of treatment versus basal intake, no differences were found (Tukey's p=0.82, ns). In contrast, vehicle-treated stressed animals showed very little sucrose intake.

[0066] Male rats that were not exposed to CMS showed a stable intake of water and sucrose solution throughout the 6 weeks of evaluation. Likewise, the group of non-stressed rats that received the combination of mirtazapine and venlafaxine showed no change in fluid intake (2-way RM ANOVA: time: F6,84 =1.025, p=0,.1 ; treatment: F1 ,14 =1 ,.6, p=0,.8; interaction: F6,84 =1 ,.6, p=0.38) (Figure 2b) (Figure 2b).

[0067] Example 4. Effect of chronic administration of the combination of mirtazapine and venlafaxine in the CMS model in female rats. Female rats also reduced their intake of sucrose solution during the CMS protocol, and there was a gradual increase in sucrose preference with mirtazapine / venlafaxine treatment. Twenty-eight rats were used in the sucrose adaptation period, and 26 (92%) developed sucrose preference. In contrast to the males, after three weeks of CMS exposure, 16 of the 26 females met the criteria for anhedonia and began treatment with the combination of mirtazapine and venlafaxine or vehicles. After two weeks of treatment, the group of rats receiving the antidepressant combination began to regain a preference for sucrose solution (p<0.05 vs. the vehicle- treated stressed group), and this preference was even greater at the end of the third week (p<0.0001), and sucrose intake was similar to that measured at baseline (Tukey's p=0.79, ns). Statistical results showed a significant difference between factors (RM two-way ANOVA: time: F6,84 =18.75, p<0.0001 ; treatments: F1 ,14 =10.55, p=0.005; interaction: F6,84 =2.88, p=0.01) (Figure 3a). Meanwhile, female rats injected with vehicles did not regain sucrose preference.

[0068] In the female groups that were not exposed to CMS, sucrose and water intake remained stable during the six weeks of the experiment, regardless of the treatments received. This confirmed that the combination of mirtazapine and venlafaxine did not modify fluid intake (two-way RM ANOVA: time: F6,84 =763, p=0.6; treatments: F1 ,14 =0.005, p=0.94; interaction: F6,84 =0.599. p=0.72) (Figure 3b) (Figure 3b).

[0069] The comparison between sexes in the antidepressant effect of the combination of mirtazapine plus venlafaxine yielded interesting results. The comparison between sucrose intake before and after treatment between sexes showed no differences (Mann-Whitney, U= 20, p=0.22, ns): the value of sucrose intake in females at the beginning of treatment (week 3) was 4.11 ± 0.42 g, while at the end of treatment (week 6), it increased to 8.41 ± 1.45 g. In males, these values were 2.33 ± 0.12 g at the start of treatment (week 4), while at the end of treatment (week 7), it increased to 6.98 ± 0.50 g. However, the time course of the antidepressant effect of this combination shows sex differences: in males, already two weeks after treatment (week 6) there was a sucrose consumption similar to that shown at basal levels (Figure 2a, Tukey p=0. 61 , ns), while in females, after two weeks of treatment (week 5), there was a slight increase in sucrose consumption which, however, remained different from basal levels of sucrose intake (Figure 3a, Tukey p<0.001).

[0070] Example 5. Sexual behavior of male rats after chronic administration of the combination of mirtazapine and venlafaxine. To evaluate the putative effects of this antidepressant combination on male sexual behavior, we used sexually experienced males that ejaculated at least twice (range 2 to 5 ejaculations) during the 30-min test. For this reason, sexual behavior parameters were determined for the first two copulatory series.

[0071] When administered for 21 days, the combination of mirtazapine and venlafaxine of the invention did not change the number of ejaculations achieved in 30 minutes compared to the vehicle-treated group (U=32; p=0.99) (Figure 4a). A different situation occurred with intromission latency, which was reduced in the drug-treated animals (U=10.5; p=0.023) (Figure 4b). Likewise, antidepressant treatment did not modify the number of mounts (S1 : U=28.5; p=0.74; S2: U=28; p=0.69) (Figure 4c), but increased the number of intromissions, and this elevation was greater in the first (U=7.5; p=0.008) than in the second ejaculatory series (U=13; p=0.04) (Figure 4d). Finally, no differences were found in ejaculatory latencies (S1 : U=28, p=0.70; S2: U=29, p=0.77) (Figure 4e).

[0072] Since the number of intromissions increased in drug-treated males, but no changes in ejaculation latencies were found, the interval between intromissions (III) was calculated. No statistically significant differences were found between the III of antidepressant- and vehicle-treated animals (S1 : U= 15; p=0.08; S2: U= 17, p= 0.13) (data not shown), although a trend toward reduction was observed in the group receiving mirtazapine plus venlafaxine. Post ejaculatory intervals were also unchanged (S1 : U=28, p=0.72; S2: U=13, p=0.29) (data not shown). It is worth mentioning that the post ejaculatory interval of the second ejaculatory series was calculated based on seven animals in the treated group, and six animals in the vehicle group, since only these rats resumed copulation after the second ejaculation.

[0073] Example 6. Sexual behavior of the female rat after chronic administration of the combination of mirtazapine and venlafaxine. All female rats used in the experiment presented regular estrous cycles of 4-5 days over 14 days prior to the administration of the antidepressants or vehicles (data not shown). During treatment, no differences were found in the number of different phases of the estrous cycle exhibited by control and drug-treated females (Figure 5a); i.e. , the regularity of the estrous cycle was not altered by this combination of antidepressants. This lack of effect made it possible to evaluate the sexual behavior of females under natural conditions, i.e., during the late proestrus phase.

[0074] Figure 5b compares the number of jumps, darts and ear wiggles between control and selected drug- treated females in proestrus. No changes in the number of these proceptive behaviors were found after antidepressant treatment (jumping: U=12, p=0.06; darting: U=16, p=0.16; ear wiggling: U=17.5, p=0.23). Receptivity was also not altered by treatment with the combination of mirtazapine plus venlafaxine. All female rats in both groups presented a lordosis quotient of 100 (U=28, p=0.99) (Figure 5c). Online, lordosis intensity did not differ between vehicle- and antidepressant-treated groups (U=12, p=0.07) (Figure 5d).

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Claims

Claims.1 . A pharmaceutical composition for the treatment of depression and without altering sexual behavior, characterized in that it comprises mirtazapine (MTZ), venlafaxine (VLF) and a pharmaceutically acceptable vehicle.

2. The pharmaceutical composition according to claim 1 , characterized in that mirtazapine (MTZ) is at a concentration of 5 mg / kg and venlafaxine (VLF) is at a concentration of 7.5 mg / kg.

3. A pharmaceutical composition comprising mirtazapine (MTZ), venlafaxine (VLF) and a pharmaceutically acceptable vehicle, for use in the treatment of depression and without altering sexual behavior.

4. The pharmaceutical composition for use according to claim 3, wherein mirtazapine (MTZ) is at a concentration of 5 mg / kg and venlafaxine (VLF) is at a concentration of 7.5 mg / kg.

5. The use of a combination of mirtazapine (MTZ) and venlafaxine (VLF), for the manufacture of a drug for the treatment of depression and without altering sexual behavior.

6. The use in accordance with claim 5, wherein the mirtazapine (MTZ) is at a concentration of 5 mg / kg and the venlafaxine (VLF) is at a concentration of 7.5 mg / kg.

7. A method for the treatment of depression without altering sexual behavior, characterized in that it comprises the step of administering to a patient suffering from said condition the composition in accordance with claim 1 to 2.

8. The method in accordance with claim 7, characterized in that the composition of administered subchronically.

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