UA81248C2 - Combination therapy wherein a serotonin reuptake inhibitor is used and compounds, which are a gabab receptor antagonist, inverse agonist or partial agonist - Google Patents

Abstract

The invention relates to the use of a compound, which is a serotonin reuptake inhibitor, and another compound, which is a GABAB receptor antagonist, inverse agonist or partial agonist for the preparation of a pharmaceutical composition for the treatment of depression, anxiety disorders and other affective disorders, such as generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post traumatic stress disorder and social anxiety disorder, eating disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, drug abuse or any other disorder responsive to serotonin reuptake inhibitors.

Description

Description of the invention

This invention relates to a combination of a serotonin reuptake inhibitor and a GABABv receptor antagonist. Accordingly, this invention relates to the use of certain compounds and to compositions of compounds having serotonin reuptake inhibitory activity, and antagonistic, partial agonistic, or inverse agonistic activity against GABA receptors, for the treatment of depression and other affective disorders. Combined serotonin reuptake inhibitory effect and antagonistic, partial antagonistic and reverse antagonistic effect on GABA receptors can have the same chemical structural unit 70 or two separate chemical structural units.

Selective serotonin reuptake inhibitors (SSRIs) have become first-choice therapeutics in the treatment of depression, certain forms of anxiety, and social phobias because they are effective, well tolerated, and have a favorable safety profile compared to classic tricyclic antidepressants.

However, clinical studies of depression and anxiety disorders have shown that there is a significant number of cases of non-responsiveness to NSAIDs, up to 3095. Another factor in antidepressant treatment that is often neglected is the patient's compliance with the prescribed treatment regimen, which has a strong influence on motivation of the patient to continue drug therapy.

First of all, there is a delay in the therapeutic effect of 55KI. Sometimes the symptoms of the disease even worsen during the first weeks of treatment. Secondly, sexual dysfunction is a side effect common to all Z5OCIs. Without adequate attention to these issues, real progress in drug therapy for depression and anxiety disorders is unlikely.

In order to overcome the lack of appropriate response to treatment, in some cases psychiatrists use reinforcement strategies. Enhancement of therapy with antidepressants can be carried out with the help of co-administration of mood stabilizers, such as lithium carbonate or triiodothyronine, or the use of Ge) electroshock.

In 1993, a pindolol augmentation strategy was described (Apidase et al). in Tgepaz RIagtasoi. Zoi., 1993, 14; pp. 262-263). The idea of Apidaz is based on experiments with intracerebral microdialysis in animals.

In fact, later neurochemical studies based on the hypothesis of desensitization by Wieg and co-authors indicated that the delay in the therapeutic effect of antidepressants is associated with the gradual desensitization of 5-HT autoreceptors. 9. Si. RvzusirpagtasoI. 1987, 7 zirri. 6,245-355).

The key point in their hypothesis is that the effect of Z5KI on the release-regulating somatodendritic autoreceptors (5-HT.d) limits the release of 5-HT in the terminal areas and, thus, the effect of inhibition "-- capture of 5-HT in the indicated areas. This is confirmed by microdialysis experiments in rats, which show 325 that the increase in the level of extracellular 5-HT, caused by a single dose of Z5KI, is enhanced by the co-administration of a 5-HTd autoreceptor antagonist. (Ipmegpigli eika). Vgaip Caves, 1992, 584, p. 322-324 and Niopy, 5., 9.

Meshygospet, 1993, 60, pp. 776-779).

The effect of the combined administration of a compound that inhibits the reuptake of serotonin and an antagonist of the 5-HT/d receptor was evaluated in several studies (pp. RIPaptaso!i 1987,143, pp. 1095-204 and Sagivide 5.E. Hg. in. Rnaptasoi. 1995, 775, pp. 1064-1070, Viiiieg R. et al. Tgtepavz ip RIagptasoi. with Zsiepse 1994, 75,220). In these studies, it was established that 5-HT/d-receptor antagonists will remove

From" the initial inhibition of neurotransmission involving 5-HT, induced by serotonin reuptake inhibitors, and thus lead to an immediate acceleration of neurotransmission involving 5-HT and a rapid onset of therapeutic action.

Several patent applications have been filed relating to the use of a combination of a 5-HT receptor antagonist and a serotonin reuptake inhibitor for the treatment of depression; see, for example, EP-A2-687,472 and EP-A-714,6631.

Another approach to increasing 5-HT in the terminals is blockade of the 5-HT 4b-autoreceptor. Indeed, in experiments with microdialysis on rats, it was shown that the increase in the level of 5-HT in the hippocampus under the influence of citalopram is enhanced by OMS "iz" 20 2-29, which is an experimental antagonist of the 5-HT v-receptor.

Several patent applications have also been filed covering the combination of Z5KI and an antagonist or partial co-agonist of 5-HT receptors (MO 97/28141, UMO 96/03400, EP-A-701819 and UMO 99/138771. u"Aminobutyric acid ( GABA) is the most important inhibitory neurotransmitter in the brain; up to 50,905 of all central synapses are GABA-ergic |Raghedez KO, and Adto A., Meshygozsiepse and Viorepamioiga!Kemiemuv, moyo! 16: 29 rr 145-170 (1992).

HF) II norepinephrine, dopamine, and serotonin (5-HT) are under the inhibitory control of GABA (|Naegieiu MU. Te t goYe oi SAVA ip aphioiuis/apiidergezzapi agod asiop. EPok MM, Neai! 0.3. 5 Maggdep S A. (eaz), pp. 151-168, add

MMyPeu and Bop5, Mem MZhogkK (1992). There are 2 subtypes of GABA receptors, GABAc and GABAcv, which have been intensively studied, and their effects on nerve function and 5-HT release have been studied. 60 Thus, stimulation of GABAd receptors with the agonist muscimol reduced the activity of 5-HT cells and the release of 5-HT in the nuclei of the suture (Gao K. 5 Acegrasp 5.8. U. Rezusporpagtasiodu mo! 14(2): pp 100-113 (2000)), and blockade of GABA receptors increases release and subsequently increases extracellular levels of 5-HT | see below - bicuculline and

Tao K. ei ai., Vgyivy doigpai! oi Rpagtasoyodu my 119: pp. 1375-1384 (1996)).

The GABA agonist baclofen caused a decrease in the content of 5-HT in the suture and a decrease in the forebrain. oh Rpaptasiodu mo! 119: pp. 1375-1384 (1996)), and when administered separately, the GABA antagonist faclofen has no effect on the levels of 5-HT as in the seam (Abeyiap M.T. Tao MK. below and Tao K. ei ai, Vgyizy doigpa! oh Rpaptasiodu mo! 119: pp. 1375-1384 (1996)). However, faclofen administered either centrally in the hippocampus or systemically was shown to significantly increase the effect of citalopram on extracellular 5-HT levels, as shown in the data presented in the application.

The essence of the invention

Now, unexpectedly, it was found that the GABA antagonist enhances the effect of 55KI on extracellular levels of 5-HT.

Therefore, it is assumed that a combination of a Z5KI and a GABA antagonist, or a molecule that has both 5-HT reuptake inhibitory and GABAergic antagonistic properties, has better efficacy and a faster onset of action than a single Z5KI.

Claimed antagonism of any GABA splice variants in, including but not limited to,

GAMKevza and GAMKevz.

The present invention covers ZZKI together with a GABA antagonist both in separate molecules and in the same /5 molecule.

The present invention therefore provides the following.

Use of an antagonist, inverse agonist or partial agonist of GABA receptors for the preparation of a pharmaceutical composition for use in combination with a serotonin reuptake inhibitor (SRI).

This invention relates to the use of a compound that is a serotonin reuptake inhibitor and another compound that is an antagonist, inverse agonist or partial agonist of GABA c receptors for the preparation of a pharmaceutical composition for the treatment of depression, anxiety disorders and other affective disorders such as generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, appetite disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, drug addiction, or any other disorder sensitive to serotonin reuptake inhibitors. and)

This invention also relates to the use of an antagonist, inverse agonist or partial agonist of GABA receptors for the preparation of a pharmaceutical composition suitable for enhancing and/or providing a faster onset of therapeutic action of a serotonin reuptake inhibitor. In a preferred embodiment, the invention relates to the above application, in which a serotonin reuptake inhibitor is used to treat depression, anxiety disorders and other affective disorders, including generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder or social anxiety disorder, eating disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, -- cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, salt addiction, or any other a disorder sensitive to ZKI.

In another embodiment, the invention relates to the use of a) a compound that is a serotonin reuptake inhibitor and an antagonist, inverse agonist or partial agonist of GABA receptors or "

B) a combination of a compound that is a serotonin reuptake inhibitor and a compound that is an antagonist, inverse agonist or partial agonist of GABA receptors for the preparation of a pharmaceutical composition or set (set of parts) suitable for the treatment of depression, ;" anxiety disorders and other affective disorders such as generalized anxiety disorder, panic anxiety, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, appetite disorders such as bulimia, anorexia and obesity, phobia, dysthymia,

Go! premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, drug addiction, or any other disorder sensitive to serotonin reuptake inhibitors. In two independent embodiments, the invention relates to the use of a compound that is a serotonin reuptake inhibitor and a compound that is an antagonist, inverse agonist, or partial agonist of GABA receptors, for the preparation of: (a) a pharmaceutical composition or (B) a kit, suitable for the treatment of depression, anxiety disorders and other affective disorders such as generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, appetite disorders such as bulimia, (F) anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, drug addiction, or any other disorder sensitive to serotonin reuptake inhibitors. In another embodiment, the invention relates to a pharmaceutical composition or kit, which includes: a) a compound that is a serotonin reuptake inhibitor and an antagonist, inverse agonist or partial agonist of GABAc receptors, or

B) a combination of a compound that is a serotonin reuptake inhibitor and another compound that is an antagonist, inverse agonist, or partial agonist of GABA 65 receptors and optionally pharmaceutically acceptable carriers or diluents.

In two further embodiments, the invention relates to either a pharmaceutical composition or a kit comprising a compound that is a serotonin reuptake inhibitor and another compound that is an antagonist, inverse agonist or partial agonist of GABA receptors, and optionally pharmaceutically acceptable carriers or diluents.

In yet another embodiment, the invention relates to a method of treating depression, anxiety disorders and other affective disorders such as generalized anxiety disorder, panic disorder, obsessive compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, appetite disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder with 7/0 hyperactivity, drug addiction, or any other disorder sensitive to serotonin reuptake inhibitors that contains human administration , requiring this, a therapeutically effective amount of a) a compound that is a serotonin reuptake inhibitor and an antagonist, inverse agonist or partial agonist of GABAc receptors, or

B) a combination of a compound that is a serotonin reuptake inhibitor and another compound that is an antagonist, inverse agonist, or partial agonist of GABAc receptors.

Any mention of each of the following: a) a compound that is a serotonin reuptake inhibitor and an antagonist, inverse agonist, or partial agonist of GABA receptors,” and

B) the combination of a compound that is a serotonin reuptake inhibitor and (or another) compound that is a 2o antagonist, inverse agonist or partial agonist of GABA receptors should be understood as a separate variant of implementation. Accordingly, each of them can be declared separately.

It is understood that each of the medical indications is depression, anxiety disorders and other affective disorders, including generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, appetite disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, addiction to drugs or any other disorder, and) sensitive to ZK - should be understood as a separate implementation option. Accordingly, at any mention in this description, each of the indications defined above may be claimed separately.

Any mention of these indications - depression, anxiety disorders and other affective disorders, including generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, eating disorders such as bulimia, - anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, addiction to drugs or any other disorder sensitive to ZKI - in connection with the use of an antagonist, inverse agonist or a partial agonist of GABA and ZKI receptors, a pharmaceutical composition, a set, a method of treatment and a method of identification of compounds suitable for treatment should be understood as a separate variant of implementation. Accordingly, each of the indications listed above can be separately claimed together with the indicated use of the antagonist, inverse agonist or partial agonist of GABA and ZKI receptors, pharmaceutical composition, kit, method of treatment and method of identification of compounds suitable for treatment. "

In a specific embodiment, a selective serotonin reuptake inhibitor is used with c according to the invention. . In another specific embodiment, a compound that is selective for GABA receptors is used according to the invention.

In yet another embodiment, a compound that is an antagonist, inverse agonist of GABA receptors in,

It is used according to the invention. o A pharmaceutical composition or kit according to the invention can be administered by simultaneous administration.

The term "simultaneous administration" used means that the antagonist, inverse agonist, or partial agonist of GABA and 5KI receptors is administered with a time interval of no more than 15 minutes, such as no more than 10 minutes, such as no more than 5 minutes, or such like no more than 2 minutes. Antagonist, inverse agonist. or partial agonist of GABAc receptors and ZKI can be contained in "the same standard dosage form" or in "discrete dosage forms". As used, the term "same standard dosage form" means a dosage form that includes both a ZKI and an antagonist, inverse agonist, or partial agonist of GABAc receptors. The term "discrete dosage form" used means that the antagonist, inverse agonist or partial agonist of GABA receptors is contained in one dosage form and that 5KI is contained in another dosage form.

Simultaneous administration of an antagonist, inverse agonist or partial agonist of GABA receptors in and KI (F, is not necessarily combined with the administration of additional doses of an antagonist, inverse agonist or partial agonist of GABAdv receptors. Additional doses of an antagonist, inverse agonist or partial agonist of GABAc receptors can be administered, for example, 1, 2, 3, or 4 times a day, whereas a ZK and an antagonist, inverse agonist, or partial agonist of GABA receptors that are administered "simultaneously" can be administered one or more times a day, such as once a day or , for example, twice a day. Accordingly: - GABAc receptor antagonist, inverse agonist or partial agonist and ZKI can be administered simultaneously once daily, and additional doses of GABAc receptor antagonist, inverse agonist or partial agonist can be administered 1,2,3 or 4 times a day, for example 1,2 or 3 times a day, for example one 65 or two times a day, for example two times a day or for example o din once a day, or

- antagonist, inverse agonist or partial agonist of GABAc receptors and ZKI can be administered simultaneously twice a day, and additional doses of antagonist, inverse agonist or partial agonist of GABAc receptors can be administered 1, 2, 3 or 4 times a day, for example 1, 2 or With times a day, for example once or twice a day, for example twice a day or for example once a day.

Alternatively, the pharmaceutical composition or kit according to the invention is administered by sequential administration. The used term "sequential administration" means that one or more daily doses of an antagonist, inverse agonist or partial agonist of GABA receptors" and one or more daily doses of 5KI are administered with a time interval between two administered doses of more than 15 minutes and less than 4 hours, such such as 70 more than 2 hours and less than 4 hours, such as more than 15 minutes and less than 2 hours, such as more than 1 hour and less than 2 hours, such as more than 30 minutes and less than 1 hour, such as more than 15 minutes and less than 30 minutes. Either ZK or an antagonist, inverse agonist, or partial agonist of GABAc receptors can be administered first. Antagonist, inverse agonist or partial agonist of receptors

GABA and ZKI are contained in discrete dosage forms, which are not necessarily contained in the same container or package. It is usually possible to introduce 1, 2, 3, 4 or 5 daily doses of an antagonist, inverse agonist or partial agonist of GABA receptors" and 1 or 2 daily doses of ZK. Accordingly: - an antagonist, inverse agonist or partial agonist of GABAc receptors and 5KI can be administered once a day, and an antagonist, inverse agonist or partial agonist of GABAc receptors can be administered 1.2, 3.4 or 5 times a day, for example 1.2 , 3 or 4 times a day, for example 1, 2 or 3 times a day, for example one or two times a day, or for example twice a day, or for example once a day, or - antagonist, inverse agonist or partial agonist GABA receptors and 5VI can be administered twice a day, and an antagonist, inverse agonist or partial agonist of GABA receptors can be administered 1, 2, 3, 4 or 5 times a day, for example 1, 2, 3 or 4 times a day, for example 1 ,2 or 3 times a day, for example one or two su times a day, or for example two times a day, or for example once a day.

Accordingly, the pharmaceutical composition or kit according to the invention can be adapted for the simultaneous administration of the active ingredients or they can be adapted for the sequential administration of the active ingredients. When the pharmaceutical composition or kit is adapted for simultaneous administration, then the active ingredients can be contained in the same standard dosage form. When the pharmaceutical o

The composition or kit is adapted for sequential administration, then the active ingredients are contained in discrete dosage forms, which are not necessarily contained in the same container or package. The term "active ingredient" used by M means a 5KI or antagonist, inverse agonist or partial agonist of receptors.

GAMKVv.

The set (set of parts) includes the drug antagonist, inverse agonist or partial agonist of receptors --

GABA" in the first dosage form and ZKI in the second dosage form and a container for the contents of the first and second dosage forms specified above.

In particular, this invention relates to the use and to pharmaceutical compositions or kits comprising the following combinations:

SOR 55845 and a CI selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, dapoxetine, vilazodone, duloxetine, nefazodone, imipramine, femoxetine, and/or clomipramine; c SOR 62349 and CI selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, "» fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, femoxetine and clomipramine;

SOR 71982 and CI selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, (ee) fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, femoxetine and clomipramine; - SOR 76290 and KI selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, co fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, femoxetine and clomipramine; e COP 76291 and CI selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, o fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, femoxetine and clomipramine;

SOR 35348 and a CI selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, femoxetine, and clomipramine;

F, SOR 36742 and CI selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, co fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, femoxetine and clomipramine; in SOR 46381 and CI selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, femoxetine and clomipramine;

SOR 52432 and a CI selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, femoxetine and 65 Kclomipramine;

SOR 54626 and CI selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine,

fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, femoxetine and clomipramine;

SOR 55845, SOR 62349, SOR 71982, SOR 76290, SOR 76291, SOR 35348, SOR 36742, SOR 46381, SOR 52432 and SOR 54626 are described in Voumegu's MO document (a). Rpagtasoiiodisa! Kemieyemuz 2002, 54 Mo. 2, pp. 247-264;

ZSN 50911 and CI selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, femoxetine and clomipramine; faclofen and a ZKI selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, 7/0 Fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, femoxetine and clomipramine; saclofen and a CI selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, femoxetine and clomipramine; 2-hydroxysaclofen and a ZKI selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, femoxetine and clomipramine;

SAB 360 and CI selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, femoxetine and clomipramine.

In a final embodiment, the present invention relates to a method of identifying compounds suitable for the treatment of depression, anxiety disorders and other affective disorders such as generalized anxiety disorder, panic disorder, obsessive compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder. appetite disorders such as bulimia, anorexia and obesity, sch phobia, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, drug addiction or any other disorder sensitive to i) serotonin reuptake inhibitors , which includes, in any order: (a) measuring the ability of the test compounds to inhibit the reuptake of serotonin and selecting compounds that have IC50 values below 2OnNM; (B) measurement of the affinity of the tested compounds to GABA receptors and selection of compounds; and then measuring the effectiveness of the selected compounds at the GABA receptor and selecting compounds that are antagonists, inverse agonists at this receptor. with

Preferred GABA ligands exhibit affinities below 1.5 µM, while other preferred ligands exhibit affinities below 1.0 µM, and still other preferred ligands exhibit affinities below 500 nM. --

Compounds with an affinity below 100 OnNM are even more preferred. co

Examples of assays for the selection/detection of antagonists, inverse agonists or partial agonists of GABA receptors are, for example, the following.

A binding assay for the detection of compounds with affinity for GABA receptors is described in the documents:

IKapa her. oh 9. Med. Spent 1999, 42(11), 2053-2059; or ERgudemapa ei. and). Spigaiu 1994; 6(7); 583-589). "

Efficacy analysis for the detection of antagonists, inverse agonists or partial agonists on GABA receptors is presented, for example, in the documents: | aiYi Wgaiip Cavs. 1990, 506(2), 181-186; or

Vgashpeg-Ovbrogpe her. and). Hg. 9. Rpaptasoi. 1999, 128(7), 1370-1374). The invention also covers compounds identified according to this method, but is not limited to the specified methods of analysis.

According to the invention, it was found that the simultaneous introduction of an antagonist or an inverse agonist of the receptors

Go! GABA" and a serotonin reuptake inhibitor causes a significant increase in the level of serotonin in the terminal areas, as measured in microdialysis experiments, compared to the introduction of only one serotonin reuptake inhibitor. According to the invention, animal studies have shown that the antagonist or inverse agonist of the receptors

GABAc may provide a rapid onset of therapeutic action of serotonin reuptake inhibitors and enhance the anxiolytic potential of serotonin reuptake inhibitors. c Use of a combination of antagonist, inverse agonist or partial agonist of GABA receptors c. and a serotonin reuptake inhibitor can significantly reduce the amount of serotonin reuptake inhibitor needed to treat depression and other affective disorders, and thus can reduce the side effects caused by a serotonin reuptake inhibitor. In particular, the combination of a reduced amount of ZKI and an antagonist, inverse agonist or partial agonist of GABAc receptors may reduce the risk

F) sexual dysfunction and sleep disorders caused by SIDE. Co-administration of a GABA receptor antagonist, inverse agonist or partial agonist and a serotonin reuptake inhibitor may also be suitable for the treatment of persistent depression, i.e. depression that cannot be adequately treated by the administration of a single serotonin reuptake inhibitor.

Usually, a GABAergic receptor antagonist, inverse agonist, or partial agonist can be used as an adjunctive treatment to enhance the response to a CKI in patients who have not achieved at least a 40-60905 symptom reduction during the first 6 weeks of CKI treatment.

Compounds that are both serotonin reuptake inhibitors and antagonists, inverse agonists, or partial agonists of GABAc receptors may have the same pharmacological benefits as the combination of a serotonin reuptake inhibitor and antagonists, inverse agonists, or partial agonists of GABAc receptors, with respect to reduction of side effects, rapid onset of action and in the treatment of patients resistant to therapy.

Many antidepressants with serotonin reuptake inhibitory action have been described in the literature.

Any pharmacologically active compound that either primarily or partially exerts its therapeutic effect by inhibiting the reuptake of serotonin in the CNS may benefit from potentiation by an antagonist, inverse agonist, or partial agonist at GABAc receptors.

The following list contains a number of serotonin reuptake inhibitors that may benefit from GABA receptor antagonist, inverse agonist, or partial agonist enhancement: citalopram, 7/0 escitalopram, fluoxetine, K-fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, desmethylvenlafaxine, duloxetine, dapoxetine , vilazodone, nefazodone, imipramine, imipramine-M-oxide, desipramine, pyrandamine, dazepinil, nefopam, befuralin, fezolamine, femoxetine, clomipramine, cyanoimipramine, litoxetine, ceriklamine, seproxetine, MUM 27587, MUM 27866, imeldine, ifoxetine, indeloxazin, tiflucarbine . Mem 5707, MM 2222, 1 792339, roxindole, UM 35992, 01 77, Ogd 6582, Ogd 6997, Ogud 6906, amitriptyline, amitriptyline-M-oxide, nortriptyline, SI 255.663, pirlindole, indatraline, YM 280253, 1. 285974, IM 113.821, I U 214.281, SOR 6085 A, KO 25.591, napamezole, diclofenzin, trazodone, VMMU 42.569, M5 2389, cerchloramine, nitroquipazine, ademethionine, sibutramine, desmethylsubitramine, didesmethyldonsubitramine, zoviloxamin. 2. The above compounds can be used in the form of bases or their pharmaceutically acceptable acid addition salts. Each of the serotonin reuptake inhibitors defined above is intended to be a separate embodiment. Accordingly, each of them and its application can be declared separately.

Preferred compounds are citalopram, escitalopram, fluoxetine, K-fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, desmethylvenlafaxine, duloxetine, dapoxetine, vilazodone, nefazodone, c imipramine, imipramine-M-oxide, desipramine, pyrandamine, dazepinil, nefopam, befuralin, fezolamine, femoxetine, clomiiramine, cyanoimipramine, litoxetine, cericlamine, seproxetine, imeldine, ifoxetine, indeloxazin, (8) tiflucarbine, viqualin, milnacipran, basinaprin, alaproclat, cyanodothepine, trimipramine, quinupramine, dothiepine, amoxapine, nitroxazepine, roxindole, amitriptyline , amitriptyline-M-oxide, nortriptyline, pyrlindole, indatraline, napamezole, diclofenzine, trazodone, cerchloramine, nitroquipazine, ademethionine, sibutramine, desmethylsubitramine, sozo didesmethylsubitramine, clovoxamine, vilazodone,

M-(1-Kb-fluoro-2-naphthalenyl)methyl|-4-piperidinylamino|carbonyl|-3-pyridinecarboxamide (MU 27587), -

Itran-6-(2-chlorophenyl)-1,2,3,5,6,10B-hexahydropyrrolo(2,1-a)isoquinoline (Mem 5707), (hydrochloride su aI-4-exo-amino-8-chlorobenzo -(5)-bicyclo|3.3.1) nona-2-6 alpha(10 alpha)-diene) (Ogo 6997), hydrochloride (4I)-(5 alpha, 8 alpha, 9 alpha)-5,8,9 . 1(2H)-pyridinyl|ethyl|-3-isopropyl-6-(methylsulfonyl)-3,4-dihydro o-1H-2,1,3-benzothiadiazine-2,2-dioxide (! 393558),

I4-(5,6-dimethyl-2-benzofuranyl)piperidine) (COP 6085), dimethyl-|5-(4-nitrophenoxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ilyamine (KO 25.591) « shi s z (ee) - name) iz 50

IR e)

F) name) 60 b5

-Zh (А 80426), Fr

Ku er (EMO 86006), o s zo « g (2,0) (533005), « t s z so 45 ime) toy

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si and re 70 u o - (ORS 14523),

N i n s (8) o 4 o sh t s (Mem 5632), « s kl chi:

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V shi s sin hu E (UM 35992), p (ee) - M- on yu I t-ch drnpofa

IR e) )

F) In 7 / a (Ote 5582), 60,

The above compounds can be used in the form of bases or their pharmaceutically acceptable acid addition salts. Each of the serotonin reuptake inhibitors defined above is intended to be a separate embodiment. Accordingly, each of them and the application of each of them can be claimed 65 separately.

Other therapeutic compounds that may benefit from potentiation by antagonists, inverse agonists, or partial agonists of GABA receptors include compounds that cause an increase in extracellular 5-HT levels in the synaptic cleft, although they are not serotonin reuptake inhibitors. One such compound is tianeptine.

Accordingly, compounds other than PPIs that can cause an increase in extracellular serotonin levels can be used instead of PPIs in each aspect of the invention as described.

The above list of serotonin reuptake inhibitors and other compounds that cause an increase in the extracellular level of serotonin cannot be considered as limiting.

ZKIs that are particularly preferred in relation to the present invention include citalopram, escitalopram, 70 fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, femoxetine and clomipramine.

The term "selective serotonin reuptake inhibitor" (SSRI) means an inhibitor of monoamine transporters that have a stronger inhibitory effect on the serotonin transporter than on the dopamine and norepinephrine transporters. Citalopram, escitalopram, 7/5 Fluoxetine, fluvoxamine, sertraline, duloxetine, vilnazodone and paroxetine are especially preferred Z5KI according to the invention.

In certain specific embodiments, citalopram or escitalopram are used.

The following list contains a number of antagonists, partial agonists or inverse agonists of GABA receptors that can be used according to the invention; СОР-71982, СОР-76290, СОР-76291, СОР-35348,

СОР-36742, СОР-46381, СОР-52432, СОР-54626, СОР-55845, СОР-62349, СН 50911, САБЗ-360, faclofen, 2о saclofen, 2-hydroxysaclofen. Each of the above-defined antagonists, partial agonists or inverse agonists of GABA receptors is intended to be a separate embodiment. Accordingly, each of them can be declared separately.

In a preferred embodiment, the GABA receptor ligand is selected from COP 71982, COP 76290, COP 55845 and

SOR 62349. p

In specific individual variants of the implementation, faclofen, 2-hydroxysaclofen, or COP 46381 is used. o

When mentioned, each of the terms "GABAc receptor antagonist, partial agonist or inverse agonist", "GABAc receptor antagonist, partial agonist or inverse agonist", "GABA ligand" and "GABAc receptor ligand" means a GABAc receptor antagonist, GABAc receptor partial agonist and inverse agonist of GABAc receptors, each of which is intended to be a separate embodiment. Accordingly, each of the specified implementation options and their application can be declared separately. -

A specific embodiment relates to a GABA receptor antagonist and its use. with

Pharmaceutical compositions

Each of the active ingredients according to the invention can be administered either separately or together or in combination with pharmaceutically acceptable carriers or excipients in one or multiple doses. co

Pharmaceutical compositions according to the invention may be prepared with pharmaceutically acceptable carriers or diluents, as well as with any other known adjuvants and excipients according to conventional techniques, such as those disclosed in Ketipdiop: |Ppe Zsiepse i Rgasiise oi Rpaptasu, 19 Ediope,

Seppago, Ed., Musk Rybiizpipd So., Eaviop, RA, 1995). "

Pharmaceutical compositions may be, in particular, specially formulated for administration by any suitable route, such as oral, rectal, intranasal, pulmonary, topical (including buccal and

And sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral and? (including subcutaneous, intramuscular, submucosal, intravenous and intradermal) routes, with the oral route being preferred. It should be understood that the preferred path depends on the general condition and

The age of the individual being treated, the nature of the condition to be treated, and the particular active selected

Go! ingredient or active ingredients.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, pills, dragees, pills, tablets, powders and granules. If appropriate, they can be made with coatings,

GIs such as enteric coatings or can be formulated to provide controlled release of one or more active ingredients, such as sustained or sustained release, according to methods well known in the art. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous solutions for injections, dispersions, suspensions or emulsions, as well as sterile powders that should be dissolved in sterile solutions for injections or dispersions before use. Compositions for injections in the form of depots are also (F) envisaged as being within the scope of the present invention. Other suitable forms of administration include suppositories, aerosols, ointments, creams, gels, inhalation preparations, dermal patches, implants, etc. Pharmaceutical compositions of the present invention or those prepared in accordance with the present invention can be administered by any suitable route, for example, orally in the form of pills, capsules, powders, syrups, etc., or parenterally in the form of solutions for injections. such compositions can be prepared by methods well known in the art and any pharmaceutically acceptable carriers, diluents, excipients or other additives commonly used in the art can be used.65 A typical oral dosage of each of the active ingredients ranges from about 0.001 to about 100Omg/kg of body weight per day, preferably from about 0.01 to about B5Omg/kg of body weight per day, and more preferably from about 0, 05 to about 1Omg/kg of body weight per day, administered in one or more doses, for example, in 1-3 doses. The exact dosage will depend on the frequency and route of administration, the sex, age, weight, and general condition of the individual being treated, the nature and severity of the condition being treated, and any comorbidities being treated, and other factors apparent to those skilled in the art. this industry.

For parenteral methods of administration, such as intravenous, subcutaneous, intramuscular and similar administrations, doses are usually on the order of about half the dose used for oral administration.

The compositions of this invention are generally used in the form of a free substance or its pharmaceutically acceptable salt. One example is a base-addition salt of a compound used as the free acid.

When the active ingredient contains a free acid, then such salts are obtained by conventional treatment of a solution or suspension of the free acid of the active ingredient with the chemical equivalent of a pharmaceutically acceptable base.

For parenteral administration, solutions of one or more active ingredients in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E, or sesame or peanut oil can be used. /5 If necessary, such aqueous solutions should be suitably buffered and the liquid diluent first made isotonic with a sufficient amount of saline or glucose. Aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intra-abdominal administration.

The sterile aqueous media used can be readily obtained by standard techniques known to those skilled in the art. Solutions for injections can be obtained by dissolving one or more active ingredients and possible additives in part of the solvent for injection, preferably sterile water, bringing the volume of the solution to the desired volume, sterilizing the solution and filling the appropriate ampoules or bottles with it. Any suitable additive commonly used in the art, such as isotonicity agents, preservatives, antioxidants, etc., may be added.

Suitable pharmaceutical carriers include inert solid diluents or excipients, sterile aqueous suspensions, and various organic solvents.

Examples of solid carriers are lactose, kaolin, sucrose, cyclodextrin, talc, agar, pectin, gum arabic, (8) stearic acid and lower alkyl cellulose ethers, corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums, etc.

Any other adjuvants or additives commonly used for such purposes may be used, such as dyes, flavorings, preservatives, etc., provided that they are compatible with the active ingredient or ingredients used. "

Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene, and water. Likewise, the carrier or diluent may include any sustained release material known in the art, such as glycerol monostearate or glycerol distearate, alone or mixed with a wax. co

Pharmaceutical compositions formed by combining one or more active ingredients of the invention with pharmaceutically acceptable carriers are then easily administered in various dosage forms corresponding to the described routes of administration. For convenience, the compositions may be presented in a standard dosage form by methods known in the art of pharmacy. "

The active ingredients of the invention can be composed in the same or different pharmaceutical compositions and their pt") with standard dosage forms.

If the solid carrier is used for oral administration, the preparation may be in the form of a pill, a powder placed in a hard gelatin capsule, or a pill, or it may be in the form of a lozenge or tablet.

The amount of solid carrier varies widely, but usually ranges from about 25 mg to about g.

Go! If a liquid carrier is used, the drug may be in the form of a syrup, emulsion, soft gelatin capsule, or a sterile injectable form such as an aqueous or non-aqueous liquid suspension or solution. - If desired, the pharmaceutical composition of the invention may include one or more active ingredients in combination with additional pharmacologically active substances, such as the substances described above.

Brief description of illustrative materials in Fig. 1. The effect of local administration of bicuculline (HOMcM) followed by systemic administration of citalopram (1 µmol/kg subcutaneously).

Fig. 2. Effect of local administration of faclofen (50 µM) followed by systemic administration of citalopram (1 µmol/kg subcutaneously).

Fig. 3. The effect of simultaneous administration of faclofen (2 mg/kg subcutaneously) followed by systemic administration of citalopram (1 µmol/kg subcutaneously).

F) Fig. 4. The effect of administration of the GABA antagonist 2-hydroxysaclofen (2 mg/kg subcutaneously) on the citalopram-induced increase in 5-HT levels in the ventral hippocampus of rats. (1.172) - 3.01, P«0.05, citalopram 1µmol/kg subcutaneous p - 13, citalopram 1µmol/kg subcutaneous and 2-hydroxysaclofen 2mg/kg subcutaneous p - 3. in Fig.5. The effect of administration of the GABA antagonist SOR 46381 (mg/kg subcutaneously) on the citalopram-induced increase in 5-HT levels in the ventral part of the hippocampus of rats; citalopram 1µmol/kg subcutaneously on - 13, citalopram 1µmol/kg subcutaneously and SOR 46381 2mg/kg subcutaneously n - 5; citalopram 1µmol/kg subcutaneously and SOR 46381 0.5mg/kg subcutaneously n - 5; SOR 46381 1Omg/kg subcutaneously p - 2.

Fig. Effect of administration of the GABA antagonist faclofen (2 mg/kg subcutaneously) on the citalopram 65-induced increase in 5-HT levels in the prefrontal cortex of rats. (1,198) - 3.25, P«0.05, citalopram 1µmol/kg subcutaneous p - 13, citalopram 1µmol/kg subcutaneous and faclofen 2mg/kg subcutaneous p - 4.

Materials and methods

Animals

Male albino Wistar rats (285-320 g; Napap, 7ei8vi, The Netherlands) were used in the experiments.

After surgery, rats were kept individually in plastic cages (35x35x4Osm) and had free access to food and water. The animals were kept under conditions of a 12-hour light period (the light was switched on at 7:00 am). Experiments were conducted in accordance with the Declaration of Helsinki and were approved by the Animal Care Committee at the Faculty of Mathematics and Natural Sciences, University of Groningen.

Drugs 70 The following drugs were used: Citalopram hydrobromide, 2-hydroxysaclofen, SOR 46381 | iparesque

A/5, Copenhagen, Denmark), faclofen and ()-bicuculline (Zidta, BI I otsiv, USA).

Operation

Experiments on microdialysis of serotonin levels in the brain were performed using domestic I-type probes made of polyacrylonitrile/sodium methylsulfonate copolymer dialysis fiber (outer diameter 7/5 22Ωm, inner diameter 0.Zimkm, AM 69, Nogzrai, Italy). Before surgery, rats were anesthetized using isoflurane (02/M420; 300/30 Oml/min). For local anesthesia, lidocaine - НС11090о (w/v) was used. The rats were placed in a stereotaxic machine (Corey, USA) and the probe was inserted into the ventral part of the hippocampus (M. Nirro, Y 4.8 mm, IA: y3.7 mm, M: -8.0 mm) and the middle part of the prefrontal cortex (RES 1-0 .9mm;

AR: i3.5mm relative to bregma; M: -6, Ohm) (Rahipoz apa U/aizop, 1982). After the probe was inserted, it was fixed with dental cement.

Experiments on microdialysis

Rats were allowed to recover for at least 24 hours. The probes were perfused with artificial cerebrospinal fluid containing 147mM Masi, 3.0mM KSI, 1.2mM Sasi" and 1.2mM MosSi" at a flow rate of 1.5ml/min. (Nagmaga arragaiv5, Zotsii Maiysk, MA., OBA). 15-minute microdialysis samples were collected in HPLC vials containing 7.5 μl of 0.02 M acetic acid for serotonin analysis.

Analysis of serotonin: i)

Microdialysis samples of 20 μl were injected using an auto-injector (cooled device for taking samples СМА/200, СМА, Sweden) onto a column Zmkm 100 x 2.0 mm C18 Nuregzi! (Wesieg, Atwieimeep, The Netherlands) and separated with a mobile phase consisting of 5g/l diammonium sulfate, 50mg/l EDTOC (EOTA), 5mg/l sodium heptanesulfonic acid, 495 vol/vol methanol. and ZoOmcl/l of triethylamine, pH 4.65 at a flow rate of 0.4 ml/min. (Zpitadli 0-10 AB), 5-HT was detected amperometrically on a glass carbon electrode at 500mV in comparison with La/Aos! (Apies I eudepe, I eidepe, Netherlands). The limit of detection was equal to 0.5 fmol of 5-NO sample in a volume of 20 μl (signal/noise ratio 3).

Data presentation and statistics --

Four consecutive microdialysis samples with a difference of less than 2095 were taken as controls and taken as 10095. Data are presented as percentages of the control level (mean - standard error) over time. Statistical analysis was performed using the program 5bidtaviai tog MUipasmuv (ZR, Uapaei

Sogrogayop). Treatments were compared with controls using two-way ANOVA for repeated measures followed by the Student-Newman-Keuls test (Zimdepi Mem/tap Ketsiv). The level of significance of the differences was equal to rО0.05. Results and Local administration of the GABA antagonist bicuculline followed by systemic administration of citalopram (Fig. 1). "" Local injection of 50 μM bicuculline into the ventral part of the hippocampus increased serotonin levels by approximately 15095 (time treatment effect; (1.79) - 5.20, P - 0.0003). Retrospective analysis revealed the significance of differences from Y - 45 to 9Okhv. o The increase caused by systemic administration of 1 µmol/kg citalopram subcutaneously was not affected by local administration of bicuculline (treatment; K(1,10) - 4.64, P - 0.0567). - Local administration of the GABAc antagonist faclofen followed by systemic administration of citalopram (Fig. 2) and Local administration of the GABAc antagonist faclofen had no effect on the basal levels of 5-HT in the ventral 5o part of the hippocampus (P(1.9) - 1.44, P - 0.26). Systemic administration of citalopram during local administration of faclofen caused an increase in 5-HT levels (treatment K(1,9) - 12.21, P - 0.0068, effect of treatment over time; coE(1,112) - 5.03, P "0.0001). Significant differences during the retrospective analysis were achieved from i - 75 to 15 Ohv.

The effect of simultaneous administration of faclofen (2 mg/kg subcutaneously) with citalopram (1 μmol/kg subcutaneously) (Fig. 3)

The combined administration of faclofen (2 mg/kg subcutaneously) with citalopram (1 µmol/kg subcutaneously) caused increased levels of 5-HT compared to treatment with citalopram alone (treatment K(1.7) - 8.64, P - 0.021, (F, effect of treatment over time (1.98) - 6.38, P «0.0001). Retrospective analysis showed different effects from Her - 75 to ko 1 - 135.

The effect of simultaneous administration of 2-hydroxysaclofen (2 mg/kg subcutaneously) with citalopram (1 µmol/kg subcutaneously) is equal to that of 5-HT (Fig. 4).

Simultaneous administration of citalopram with the GABA antagonist 2-hydroxysaclofen also caused an increase in the effect on the level of 5-HT. Treatment K(1.14) - 4.80, P - 0.046, effect of treatment over time; K(1.172) - 3.01, P - 0.0018.

The effect of simultaneous administration of COP 46381 with citalopram (1 µmol/kg subcutaneously) on the level of 5-HT (Fig. 5).

Administration of a high dose of the GABAergic antagonist COP 46381 (1Omg/kg subcutaneously) did not have any effect on β5 levels of 5-HT. However, when COP 46381 (0.5 and 2 mg/kg) was co-administered with citalopram (1 µmol/kg), then an enhanced response was observed in the level of 5-HT (0.5 mg COP; treatment E(1.16) - 4.94, p - 0.04; effect of treatment over time; (1.193) - 3.24, P-0.00081); treatment with 2 mg of SOR (1.16) - 2.94, p - 0.10; effect of treatment over time;

E(1.192) - 3.79, P«0.001).

The effect of simultaneous administration of faclofen (2 mg/kg subcutaneously) with citalopram (10 kmol/kg subcutaneously) on 5-HT in the prefrontal cortex (Fig. b)

Co-administration of faclofen (2 mg/kg subcutaneously) with citalopram (1 µmol/kg subcutaneously) caused increased levels of 5-HT compared to treatment with citalopram alone (treatment E(1.15) - 4.61, P - 0.048; treatment effect by time; K(1.198) - 6.3.25 P«0.0008).

Claims (35)

The formula of the invention 1. Use of a compound that is a serotonin reuptake inhibitor and another compound that is an antagonist, inverse agonist or partial agonist of GABA receptors for the preparation of a pharmaceutical composition for the treatment of depression, anxiety disorders and other affective disorders such as generalized anxiety disorder, panic anxiety, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, appetite disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, drug addiction or any other disorder sensitive to serotonin reuptake inhibitors. 2. Application according to claim 1, where a selective serotonin reuptake inhibitor is used. C. Application according to claim 1, where a compound is used which is selective for GABA receptors. 4. Application according to claim 1 or 3, where an antagonist or inverse agonist of GABA receptors is used. 5. Application according to claim 4, where an antagonist of GABA receptors is used. high school 6. Application according to claim 1 or 2, where the CPI is selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, (o) femoxetine and clomipramine. 7. Application according to any one of claims 1 and 3-5, where the GABA receptor ligand is selected from СОР-71982, СОР-76290, СОР-76291, СОР-35348, СОР-36742, СОР-46381, СОР-52432, СОР -54626, SOR-55845, SOR-62349, ZSN 50911, SAB-360, faclofen, saclofen, 2-hydroxysaclofen. 8. Use of an antagonist, inverse agonist or partial agonist of GABA receptors in the preparation of a pharmaceutical composition for use in combination with a serotonin reuptake inhibitor. 9. Use according to claim 8, in which the serotonin reuptake inhibitor is used for -- treatment of depression, anxiety disorders and other affective disorders, such as generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, eating disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, drug addiction, or any other disorder sensitive to 5CI. "20 10. Application according to claim 8 or 9, where a selective serotonin reuptake inhibitor is used. from the village 11. Application according to claim 8 or 9, where a compound is used that is selective for GABAB receptors. 12. Application according to any one of claims 8, 9 and 11, where an antagonist or inverse agonist of GABA receptors is used. 13. Application according to claim 12, where an antagonist of GABA receptors is used. 14. Use according to any one of claims 8-10, where the ZKI is selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, femoxetine and clomipramine. - 15. Application according to any one of claims 8, 9 and 11-13, where the GABA receptor ligand is selected from SOR-71982, SOR-76290, SOR-76291, SOR-35348, SOR-36742, SOR-46381, SOR -52432, СОР-54626, СОР-55845, СОР-62349, ZСН 50911, САБ-360, faclofen, saclofen, 2-hydroxysaclofen. - 16. Use of an antagonist, inverse agonist or partial agonist of GABA d receptors for co-preparation of a pharmaceutical composition suitable for enhancing and/or ensuring a faster onset of the therapeutic effect of a serotonin reuptake inhibitor. 17. Use according to claim 16, in which the serotonin reuptake inhibitor is used for the treatment of depression, anxiety disorders and other affective disorders, such as generalized anxiety disorder, panic anxiety, obsessive-compulsive disorder, acute stress disorder, post-traumatic (PT) stress disorder and social anxiety disorder, eating disorders such as bulimia, anorexia and obesity, GI phobia, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, drug addiction, or any other disorder sensitive to 5CI. in 18. Application according to claim 16 or 17, where a selective serotonin reuptake inhibitor is used. 19. Use according to claim 16 or 17, where a compound is used that is selective for GABA receptors. 20. Application according to claim 16, 17 or 19, where an antagonist or inverse agonist of GABA receptors is used. 21. Application according to claim 20, where an antagonist of GABA receptors is used. 22. Use according to any one of claims 16-18, where the ZKI is selected from citalopram, escitalopram, fluoxetine, 65 sertraline, paroxetine, fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, femoxetine and clomipramine. 23. Application according to any one of claims 16, 17 and 19-21, where the GABA receptor ligand is selected from СОР-71982, СОР-76290, СОР-76291, СОР-35348, СОР-36742, СОР-46381, СОР- 52432, СОР-54626, СОР-55845, СОР-62349, ZСН 50911, САБ-360, faclofen, saclofen, 2-hydroxysaclofen. 24. A pharmaceutical composition comprising a compound that is a serotonin reuptake inhibitor and another compound that is an antagonist, inverse agonist, or partial agonist of GABA receptors, and optionally pharmaceutically acceptable carriers or diluents. 25. Pharmaceutical composition according to claim 24, characterized in that the serotonin reuptake inhibitor used is a selective serotonin reuptake inhibitor. 70 26. Pharmaceutical composition according to claim 24, which is characterized by the fact that the antagonist, inverse agonist or partial agonist of GABA receptors is selective for GABA receptors. 27. Pharmaceutical composition according to claim 24 or 26, which differs in that the GABA ligand is an antagonist of GABA receptors. 28. Pharmaceutical composition according to claim 24 or 25, which is characterized in that the /5 serotonin reuptake inhibitor is selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, femoxetine and clomipramine . 29. Pharmaceutical composition according to claim 24, 26 or 27, which is characterized by the fact that the GABAR receptor ligand is selected from СОР-71982, СОР-76290, СОР-76291, СОР-35348, СОР-36742, СОР-46381, СОР-52432, СОР-54626, СОР-55845, СОР-62349, СН 50911, CA5B-360, faclofen, saclofen or 2-hydroxysaclofen. 30. Pharmaceutical composition according to any one of claims 24-29, which is characterized in that it is adapted for simultaneous administration of active ingredients. 31. Pharmaceutical composition according to item 3, which is characterized by the fact that the active ingredients are contained in the same standard dosage form. 32. A combination of a compound that is a serotonin reuptake inhibitor and another compound that is a substance antagonist, inverse agonist, or partial agonist of GABA receptors, and optionally pharmaceutically acceptable carriers or diluents. and) 33. The combination according to claim 32, characterized in that it is adapted for simultaneous administration of active ingredients. 34. The combination according to claim 32, which is characterized by the fact that it is adapted for sequential administration of active ingredients. 35. The combination according to claim 32 or 34, which differs in that the active ingredients are contained in discrete dosage forms. c "- d) - c ;" (ee) - ime) iz 50 IR e) Ф) ime) 60 b5