EP2134865A2

EP2134865A2 - Novel medical diagnostic method and therapy in the context of interferon-stimulated genes that induce depression

Info

Publication number: EP2134865A2
Application number: EP08735084A
Authority: EP
Inventors: Martin Trippler; Jörg Friedrich SCHLAAK
Original assignee: Individual
Current assignee: Individual
Priority date: 2007-04-14
Filing date: 2008-04-08
Publication date: 2009-12-23
Also published as: WO2008125247A2; WO2008125247A3; DE102008017701A1; US20100248230A1

Abstract

The invention relates to a novel medical diagnostic method and therapy in the context of depression-inducing genes that are in particular stimulated by interferon. The invention relates in particular to the use of at least one depression-inducing nucleic acid molecule and/or nucleic acid molecule associated with depression, in particular a gene and/or its DNA sequence and/or its assigned RNA sequence and/or the use of a (poly)peptide coded by the nucleic acid for finding and/or providing a diagnostic method for depression or a medicament for the preventive and/or curative treatment of depression and/or for determining the risk of suffering from depression and/or for predicting the effects of individual medicaments and/or the side-effects of medicaments, in particular during treatment with interferon (e.g. during the treatment of hepatitis).

Description

New medical diagnostics and therapy in connection with interferon-stimulated depression-mediating genes

The present invention relates to the identification of genes involved in the development of, in particular, interferon-induced depression and / or endogenous depression. In this context, the present invention equally relates to a method for the identification of these genes, wherein the expression levels of the genes involved in interferon-induced depression and / or endogenous depression before and after administration of interferon, in particular α-interferon, or in subjects be determined and correlated with or without endogenous depression. In the genes thus determined, which are involved in interferon-induced depression, which are synonymously also referred to as in particular interferon-stimulated depression-mediating genes, and / or genes involved in endogenous depression are, for example, DYNLTl, MEF2A, TORIB or DISCI.

Furthermore, the present invention relates to the use of a depression-inducing or depression-associated nucleic acid molecule, in particular of a depression-inducing or depression-associated gene, for diagnosis and therapy, for predicting disease progression and / or for predicting the side effects or the response of medicaments.

In addition, the present invention relates to methods for the identification of substances which regulate the gene activity of the depression-inducing or depressionsassoziierten genes or the corresponding gene products, and a method for improving the pharmacological properties of these substances. Furthermore, the present invention relates to the use of the gene activity of a depression-inducing or depression-associated gene regulating substances in the field of diagnosis and therapy of depression.

Finally, the present invention relates to a method for determining the risk of a subject suffering from depression. In the context of the present invention, depression is preferably a depression occurring as part of the interferon-assisted therapy of hepatitis, in particular hepatitis C, as an undesired side effect of interferon therapy.

Chronic hepatitis C virus (HCV) infection is a major global health problem with approximately 170 million people infected worldwide. With a chronification rate of about 80%, hepatitis C is one of the main causes of hepatitis, liver cirrhosis and hepatocellular carcinoma. Interferon (IFN), in particular α-interferon (also known as Inter ferron-alpha or IFNα), preferably pegylated IFNα, optionally in combination with ribavirin. One of the most common side effects of this therapy is IFN-induced major depression, which, in addition to deteriorating quality of life, may lead to discontinuation or even suicide.

Various studies have found that in the context of the therapy of hepatitis type C (synonymously also called hepatitis C), in particular chronic hepatitis C, with pegylated α-interferon in the subjects in a statistically significant manner an increased education of depression of different severity occurred. In further investigations, it was even found in this regard that depressive symptoms also had a direct negative effect on the therapy with regard to the reduction of the viral load and thus negatively influenced the therapy of type C hepatitis as such. In further studies, it has been shown that the depression occurring in comparison with other side effects for the subjects or patients represents the highest burden in the context of interferon-treated type C hepatitis. For further discussion, reference may be made to the publication by Younossi, Z. et al., "The Effects of HCV Infection and Management on Health- Related Quality of Life," Hepatology, 2007, Vol. 45, pages 806-816 as well as the references cited therein.

Likewise, within the scope of the present invention, however, it may also be an endogenous depression, as stated above. Depression, which is also synonymously referred to as a depressive episode or relapsing depressive disorder, is a mental disorder requiring treatment, which is often characterized by the combined occurrence of symptoms such as impaired drive, mood restriction, restlessness and sleep disturbances. The aforementioned mood narrowing is often associated with increased irritability and anxiety, with negative thoughts and impressions often overrated and positive aspects are not perceived or considered to be accidental. Depressive disorders are often associated with physical symptoms, such as loss of appetite, weight loss, weight gain, pain in very different parts of the body, and the susceptibility to infection is often increased during a depressive episode. Depending on the severity of depression, it may be associated with latent or acute suicidality. It is believed that most of Germany's approximately 12,000 suicides each year are due to depression. Often associated with depression is the psychosocial limitation.

In the prior art, pharmacotherapy is often the drug of choice for the treatment of depression, in which case so-called antidepressant drugs are used:

These include, for example, selective serotonin reuptake inhibitors (SSRIs). They are based on the mechanism of action of a relative selective reuptake inhibition of serotonin on the presynaptic membrane, whereby a relative increase in the messenger serotonin is achieved. However, common side effects are sexual dysfunction or anorgasmia. In addition, these substances sometimes increase initial drive and only then mood-enhancing, which can lead to a higher suicide risk in the first few weeks of use. In the US, the medicines have recently been given a warning.

Furthermore, so-called tricyclic antidepressants are used.

The main drawbacks are their side effects, such as dry mouth, constipation, tiredness, muscle tremors and low blood pressure. In addition, tri- cyclic antidepressants initially boosting the drive and only then mood-enhancing.

So-called monoamine oxidase inhibitors (MAO inhibitors) which block the enzyme monoamine oxidase, which cleaves amines such as serotonin and norepinephrine, are used as a further class of substances for the treatment of depression. Patients treated with such therapeutics, however, must follow a strict low-tyramine diet to avoid a dangerous increase in blood pressure.

A disadvantage of the aforementioned substances is thus their strong side effect, and effective therapeutic success is not always guaranteed.

By contrast, the underlying mechanism of action of interferon-induced depression is not yet known. There are several hypotheses suggesting an influence of interferon on glucocorticoid or serotonin IA (5-HT) receptors. It is also believed that the administration of interferon in the treatment of type C hepatitis leads to an increase in ACTH (adrenocorticotropic hormone), cortisol and interleukin-6 levels in patients who develop depression as part of therapy with interferon. Against this background, in the state of the art, the targeted administration of selective serotonin reuptake inhibitors (SSRIs) is also proposed within the context of the therapy of the depression occurring in connection with the interferon-treated hepatitis C. Reference may be made to the publication by Horsmans, Y. "Interferon-induced depression in chronic hepatitis C", Journal of Antimicrobial Chemotherapy, 2006, Vol. 58, pages 71 1 to 713, as well as those cited therein for further related information and discussion Literature.

As regards a possible genetic predisposition to the development of depression, there is only an incomplete and non-uniform picture in the prior art, it being merely clear that there is no such thing as a single and isolated "gene of depression", but rather, in particular, a regulation of one Variety of genes can lead to the development of depression. In the prior art, it has thus far been completely unclear to what extent a specific genetic disposition contributes to the formation of an endogenous as well as an interferon-mediated depression. In particular, it has hitherto not been possible to find specific genes which influence or cause the development of depressions, in particular of interferon-mediated depression, but also of endogenous depression, namely specific genes which are involved in the formation of interferon-induced depression, in particular in the context the therapy of hepatitis type C, or an endogenous depression are involved or play a crucial role in this regard, have not been identified.

However, the identification of such genes would represent a major step in the effective treatment or treatment of depression, especially depression associated with the therapeutic administration of interferon in the treatment of type C hepatitis. In particular, for the patients already suffering from hepatitis C, the development of depression represents an additional enormous burden and an influence on the quality of life, especially since patients are already significantly weakened by the previous illness.

US 2001/0029015 A1 relates to a method for locating mutations or polymorphisms in the so-called torsin gene, in torsin-related genes and methods for detecting neuronal diseases caused by these mutations and polymorphisms. This document deals with the diagnosis of neuronal diseases based on SNP-based analyzes (single nucleotide polymorphism).

Furthermore, US 2003/0054345 A1 relates to a method and a composition for the diagnosis and treatment of neuropsychiatric disorders, such as schizophrenia. In this context, the gene DISCl is cited and the aforementioned diseases are discussed on the basis of molecular-biological investigations on DISC 1. Finally, US 2005/0255500 A1 also relates to psychiatric disorders associated with the DISC gene, in which the distribution of DISC1 in body cells is addressed.

The aforementioned prior art documents are not aimed at the targeted treatment of depression, in particular as regards the optimization of the therapy of interferon-induced depression, in particular in the context of hepatitis type C treatment, and the therapy of endogenous depression, respectively.

Against this background, it is an object of the present invention to provide novel and efficient diagnostic and treatment possibilities of endogenous and interferon-induced depression, in particular associated with excessive activity of certain genes, which has a higher level of inhibition than the approaches known in the art Efficacy to have at the same time reduced side effect.

In this context, a further object of the present invention is to provide a method with which specific genes can be identified which are decisive for the development of depression, in particular an endogenous as well as one occurring for example in the context of the therapy of hepatitis type C. , interferon-induced depression are involved.

Another object of the present invention is to provide a method for the determination of substances or substances as such, with which the gene expression or gene activity of the depression-inducing or depressionsassoziierten genes can be controlled.

Finally, it is an object of the invention to provide methods and uses of the aforementioned type which avoid or at least reduce the disadvantages of the prior art. In other words, an object of the invention is to identify relevant risk factors of interferon-induced and / or endogenous depression and to use them for the development of preventive treatment strategies.

In the context of the present invention, the Applicant has succeeded, in a completely surprising manner, for the first time in identifying genes which are associated with the development of depression, in particular interferon-induced depression but also endogenous depression. In this connection, the Applicant has found, quite surprisingly, that the development of depression occurs in connection with an increase in the specific gene activity of defined genes. The genes identified within the scope of the present invention have not hitherto been associated with the development of interferon-induced or interferon-mediated depression and serve as a basis for the early detection of interferon-mediated depression and for the provision of new drugs for the treatment of interferon-mediated depression. However, according to the invention, the identified genes can also be used as the basis for methods or medicaments of the aforementioned type in the context of therapy for endogenous depression or as a basis for the early detection of endogenous depression. Because even with regard to endogenous depression, the Applicant has - as previously stated - completely surprisingly found that there is an increase in the gene activity of certain genes. In addition, the Applicant was able to observe an upregulation of the production of interferons with regard to endogenous depression, which in turn may contribute to gene activation of certain genes.

The present invention - according to a first aspect of the present invention - is thus the use according to the invention according to claim 1, ie in other words the use of at least one depression-inducing and / or depressionsassoziierten nucleic acid molecule, in particular gene and / or its DNA sequence and / or its associated RNA sequence, and / or at least one nucleic acid-encoded (poly) peptide for finding and / or providing a diagnostic for the detection of depression and / or a drug for the prophylactic and / or curative treatment of depression and or for determining the risk of developing depression and / or for predicting individual drug effects and / or drug side effects (particularly in therapy with interferon, eg in the treatment of hepatitis).

In other words, the Applicant has surprisingly found that specific genes are involved in the development of depression, in particular interferon-induced depression. The genes are in particular:

DYNLT1, in particular with the transcript ID (locus) NM 006519, in particular according to SEQUENCE LISTING SEQ. ID. NO. 1 and / or Table 1, - MEF2A, in particular with the transcript ID (locus) NM_005587, in particular according to SEQUENCE LISTING SEQ. ID. NO. 2 and / or Table 1,

TORIB, in particular with the transcript ID (locus) NM 014506, in particular according to SEQUENCE LISTING SEQ. ID. NO. 3 and / or Table 1,

DISCl, in particular with the transcript ID (locus) NM_018662, in particular according to SEQUENCE LISTING SEQ. ID. NO. 4 and / or Table Ie 1,

GCH1, in particular with the transcript ID (locus) NM 000161, in particular according to SEQUENCE LISTING SEQ. ID. NO. 5 and / or Table 1,

ST3GAL5, in particular with the transcript ID (locus) NM 003896, in particular according to SEQUENCE LISTING SEQ. ID. NO. 6 and / or Table 1, - PSMB9, in particular with the transcript ID (locus) NM_002800, in particular according to SEQUENCE LISTING SEQ. ID. NO. 7 and / or Table 1,

- GLRX, in particular with the transcript ID (locus) NM 002064, in particular according to SEQUENCE LISTING SEQ. ID. NO. 8 and / or Table 1, RBCK1, in particular with the transcript ID (locus) NM 006462, in particular according to SEQUENCE LISTING SEQ. ID. NO. 9 and / or Table 1, and - ZNF200, in particular with the transcript ID (locus) NM 003454, in particular according to SEQUENCE LISTING SEQ. ID. NO. 10 and / or Table 1,

STAT1, in particular with the transcript ID (locus) NM 007315, in particular according to SEQUENCE LISTING SEQ. ID. NO. 1 1 and / or Table 2,

RTP4, in particular with the transcript ID (locus) NM_022147, in particular according to SEQUENCE LISTING SEQ. ID. NO. 12 and / or Table Ie 2,

UBE2L6, in particular with the transcript ID (locus) NM 004223, in particular according to SEQUENCE LISTING SEQ. ID. NO. 13 and / or Table 2,

- GBPl, in particular with the transcript ID (locus) NM 002053, in particular according to SEQUENCE LISTING SEQ. ID. NO. 14 and / or Table 2, - CCL8, in particular with the transcript ID (locus) NM 005623, in particular according to SEQUENCE LISTING SEQ. ID. NO. 15 and / or Table 2,

TNFSF 10, in particular with the transcript ID (locus) NM 003810, in particular according to SEQUENCE LISTING SEQ. ID. NO. 16 and / or Table 2, or combinations thereof.

The genes mentioned above are, as will become even more specific, depression-inducing or depression-associated genes and / or IFN-response genes whose expression correlates with IFN-induced expression.

The above SEQ ID NOS: 1 to 16 (SEQ ID NOS: 1 to 16) given under the English name SEQUENCE LISTING SEQ. ID. NO. 16), which are summarized in the appendix to the sequence listing, refer to the respective DNA sequences to the above genes. The sequence identification numbers 1 to 16 according to the sequence listing were created on the basis of a patent-legally standardized indication or representation using the software patent version 3.3.

As far as the genes mentioned above are concerned, the genes from the group of DYNLT1, MEF2A, TORIB, DISC1, GCH1, ST3GAL5, PSMB9, GLRX, RBCK1 and ZNF200 are preferably to be classified according to the invention, in particular as defined above. Because in the aforementioned genes, the applicant could determine a high influence on the development of depression, as shown in the embodiments.

Particularly preferred according to the invention are the genes from the group of DYNLT1, MEF2A, TORIB, DISC1, GCH1 and ST3GAL5, in particular as defined above. Because in the aforementioned genes, the applicant could determine a particularly high influence on the development of depression, as shown in the embodiments.

As far as the underlying depression is concerned, this is in particular a depressive disorder associated with the treatment or therapy of hepatitis, in particular chronic hepatitis type C, in which context all degrees of severity or severity of depression in the context of the present invention are understood as meaning Be considered. More specifically, depression may be a disease associated with or caused by α-interferon, in particular pegylated α-interferon, in particular wherein the depression is due to a preferably systemic administration of α-interferon , in particular pegylated α-interferon, in particular in the context of the treatment or therapy of hepatitis, especially chronic hepatitis type C, is caused.

In other words, the depression in question is, in particular, such a disease which, in connection with increased gene activity or gene expression, is at least one of the abovementioned Gene is or is caused by this. In this regard, the gene activation may for example be related to or caused by a preferably systemic administration of α-interferon, in particular pegylated α-interferon, in particular in the context of the treatment or therapy of hepatitis, in particular chronic hepatitis type C.

In addition, however, it may also be a so-called endogenous depression, which are equally related to an increased gene activity or gene expression of at least one of the aforementioned genes or can be caused thereby.

As far as the term "gene" used according to the invention is concerned, the corresponding nucleic acid molecule or the corresponding DNA sequence is likewise included in this regard. However, the use according to the invention likewise relates equally to the RNA sequence assigned to the gene, which as it were acts as a post-transcriptional product and may be, so to speak, complementary to the codogenic strand of the DNA of the gene. Likewise, in the context of the use according to the invention, the (poly) peptide encoded by the nucleic acid or the gene, in particular as previously defined, and thus to a certain extent the translation product, can also be used. The term "nucleic acid molecule" is synonymous with the term "polynucleic acid" or "polynucleic acid molecule".

As far as the use according to the invention is concerned, the depression-inducing or depression-associated gene can to a certain extent be used as the starting point for the discovery or provision of diagnostics or drugs with regard to a depression of the aforementioned type. The diagnostics or drugs may be such that they interact directly or indirectly with the depression-inducing or depressionsassoziierten gene or the RNA and / or the corresponding (poly) peptide to prevent in this way the development of depression, or at least reduce their severity. These may be substances which have a gene regulatory effect. Furthermore, the aforementioned depression-inducing or depressionsassoziierten Compounds, in particular the aforementioned genes, can be used to provide a diagnostic agent, whereby substances can be provided which, for example, enable a diagnosis of depression based on an interaction with the depression-inducing or depressions-associated genes and, for example, with increased gene activity of the depression-inducing or depression-associated genes can be inferred from the presence of depression.

As regards the use of the depression-inducing or depression-associated compounds for determining the risk of developing depression, the abovementioned substances can be used, for example, in the context of statistical analysis and evaluation methods in order to associate a patient with an increased risk, for example Depression, for example, as part of an interferon therapy to fall ill, for example, if there is an increased gene activity of the depression-inducing or depression-associated gene. Likewise, it is possible by means of the use according to the invention to predict individual drug effects, for example interferon, in particular α-interferon, preferably pegylated α-interferon, in particular with regard to the development of depression, but also of antidepressants and the like, with particular regard to avoidance of depression, or to assess their side effects.

The person skilled in the art is fundamentally familiar with the basics with regard to the specific fields of application of the use according to the invention, so that no further explanation is required in this regard.

Another object of the present invention - according to a second aspect of the present invention - is the inventive method according to claim 2, ie in other words a method for identifying an inhibitor and / or repressor of a depression-inducing and / or depressionsassoziierten nucleic acid molecule, in particular gene and / or its DNA sequence and / or its associated RNA sequence, comprising the following steps: (A) contacting the nucleic acid molecule with at least one test substance under conditions which allow an interaction, in particular binding, of the test substance (s) to the nucleic acid molecule; and (b) detecting and / or analyzing whether the test substance (s) restrict or inhibit gene activity and / or expression of the nucleic acid molecule and / or whether the test substance (s) limit or prevent the depression-inducing and / or depression-associated properties of the nucleic acid molecule.

The method according to the invention can be carried out, for example, in vitro, it being possible to investigate, as it were, an interaction of the test substance with the nucleic acid molecule or the gene and, in the case of interaction, resulting in a reduced gene activity as a result of which this interaction can be closed. The method according to the invention can likewise be carried out in a corresponding host system, wherein the host is a carrier of the depression-inducing or depression-associated nucleic acid molecule or gene and advantageously has a corresponding expression system. The method according to the invention can equally be used for the identification of IFN-response genes. The detection of the interaction or interaction or the detection of the influence of the gene activity can be carried out by methods familiar to the person skilled in the art.

In this context, according to one aspect of the present invention, the present invention relates to a method according to claim 3, d. H. In other words, a method for identifying an inhibitor and / or repressor of a (poly) peptide encoded by a depression-inducing and / or depression-associated nucleic acid molecule, in particular gene and / or its DNA sequence and / or its associated RNA sequence the following steps:

(a) contacting the (poly) peptide with at least one test substance under conditions which allow an interaction, in particular binding, of the test substance (s) to the (poly) peptide; and (B) detection and / or analysis of whether the test substance (s) restrict or prevent the depression-inducing and / or depression-associated properties of the (poly) - peptide.

The inventive method according to this aspect thus focuses on influencing the gene product. The method can be carried out in a manner known to those skilled in the art both in vitro and in vivo in a host system, wherein in the latter case the host should preferably carry the nucleic acid encoding the (poly) peptide to be examined. Equally, however, an interaction can also be carried out in vitro on isolated (poly) peptides. The method of the invention can equally be used with respect to IFN response genes.

The methods of the invention according to the second and third aspects of the present invention may be carried out by using a plurality of test substances and performing the following steps:

(a) testing various test substances in different reaction vessels, wherein those test substances which do not limit or do not prevent the depression-inducing and / or depression-associated properties of the nucleic acid molecule and / or of the (poly) peptide are no longer taken into account in the further test procedure;

(b) distribution of test substances from such reaction vessels in which a reduction or elimination of depression-inducing and / or depression-associated properties of the nucleic acid molecule and / or the (poly) peptide in step (a) has been determined, to new reaction vessels and Repeating step (a) with the new reaction vessels; and

(c) repeating step (b) until a single test substance is identified to which the reduction or elimination of depression-inducing and / or depression-associated properties of the nucleic acid molecule and / or the (poly) peptide can be assigned.

It is equally possible that the methods according to the second and third aspect of the present invention be carried out such that the test substance (s), the nucleic acid molecule and / or the (PoIy -) - Peptide are coupled to a readout system (readout system) and / or wherein the test batch a readout system is added and / or wherein the readout system after binding of the test substance (s) with the nucleic acid molecule and / or the (poly) peptide is a detectable Signal supplies.

Within the scope of the abovementioned methods, the test substances may be low-molecular substances, peptides, aptamers, antibodies and / or fragments or derivatives thereof.

As stated above, the aforementioned methods can be carried out, for example, in a host or host system, wherein the host or the host system preferably comprises the previously defined genes and has a corresponding expression system. Such hosts are familiar to the person skilled in the art or the skilled person is always able to select specific host systems in the context of the present invention, so that in this respect no further embodiments are required. The methods according to the invention can likewise be carried out in the form of high-throughput methods and / or computer-assisted.

For further details with respect to the inventive methods according to the second and third aspects of the present invention, reference may be made to the statements on the first-mentioned aspects or objects of the present invention, which apply accordingly in this regard.

Yet another subject of the present invention - according to one aspect of the present invention - is the inventive method according to claim 10, d. H. in other words, a method for improving the pharmacological properties of the test substances identified according to the previously described method according to the third aspect of the present invention, wherein

(A) identifies the binding site of the test substance to the nucleic acid molecule or to the (poly) peptide and optionally the binding site of the nucleic acid molecule or the (poly) peptide to the test substance; (b) modifying the binding site of the test substance and the nucleic acid molecule or the (poly) peptide by molecular modeling; and

(c) modifying the test substance such that its binding specificity or binding affinity or binding avidity is increased for the nucleic acid molecule or the (poly) peptide.

In this regard, the binding site in step (a) can be determined by site-directed mutagenesis, the procedures of which are known per se to those skilled in the art.

Yet another subject of the present invention - according to one of the aspects of the present invention - is the method according to the invention according to claim 12, d. H. in other words, a method for modifying a test substance which is identified or improved according to the previously defined method, wherein the test substance is further modified as a lead structure

(i) a modified active site, a modified spectrum of activity and / or a modified organ specificity and / or

(ii) an improved activity and / or

(iii) decreased toxicity (an improved therapeutic index) and / or

(iv) reduced side effects and / or

(v) a delayed onset of therapeutic efficacy and / or length of therapeutic efficacy; and / or

(vi) altered pharmacokinetic parameters (in particular absorption, distribution, metabolism and / or excretion) and / or (vii) modified physicochemical parameters, in particular solubility, hygroscopic properties, color, taste, odor, stability and / or shape, and / or

(viii) improved general specificity, organ / tissue specificity, and / or

(ix) an optimized administration form and / or route, in particular by (a) esterification of carboxyl groups and / or (b) esterification of hydroxyl groups with carboxylic acids and / or

(C) esterification of hydroxyl groups, in particular to phosphates, pyrophosphates or sulfates and / or hemisuccinates and / or

(d) formation of pharmaceutically acceptable salts and / or

(e) formation of pharmaceutically acceptable complexes and / or (f) synthesis of pharmacologically active polymers and / or

(g) introduction of hydrophilic groups and / or

(h) introduction and / or replacement of substituents in aromatics and / or side chains and / or modification of the substituent mester and / or

(i) Modification by introduction of isosteric and / or bioisosteric groups and / or

(j) synthesis of homologous compounds and / or (k) introduction of branched side chains and / or (1) conversion of alkyl substituents to cyclic analogues and / or

(m) derivatization of hydroxyl groups to ketals and / or acetals and / or

(n) N-acetylation to amides and / or phenylcarbamates and / or (o) synthesis of Mannich bases and / or imines and / or (p) conversion of ketones and / or aldehydes into Schiff bases,

Oximes, acetals, ketals, enol esters, oxazolidines, thiozolidines or combinations thereof.

It is possible in the context of the method according to the invention that the identified, improved or modified test substance, in particular the inhibitor or repressor of the aforementioned genes, is further improved pharmacologically by peptidomimetics. For further details with respect to the inventive methods according to the fourth and fifth aspects of the present invention, reference may be made to the statements on the preceding aspects of the present invention, which apply accordingly in this regard.

Yet another object of the present invention - according to a s e c h s t e n aspect of the present invention - is the use according to the invention according to claim 14, d. H. In other words, the use of an inhibitor and / or repressor of a depression-inducing and / or depressionsassoziierten nucleic acid molecule, in particular gene and / or its DNA sequence and / or its associated RNA sequence, for the preparation of a medicament for the prophylactic and / or curative treatment of Depression. The gene may also be an IFN response gene.

The genes used in the context of the use according to the invention are preferably the genes defined above. In this connection, the Applicant has surprisingly found that the genes identified by her can be chosen as the basis for a therapeutic approach to the development of depression, such as endogenous depression, and depression, especially in patients treated with interferon, In particular, α-interferon, for example, for the treatment of hepatitis type C, be treated significantly reduce or reduce.

It can also be prevented by early administration of the inhibitors or repressors in a prophylactic therapy at a very early stage, the development or the onset of depression. In this regard, a targeted pharmacological suppression of the activity of the depression-inducing or depression-associated genes, in particular as defined above, thus leads to a targeted treatment of the depression. The inhibitors or repressors used in the context of the use according to the invention may in particular be a test substance identified according to the abovementioned inventive method, which acts as an inhibitor or repressor with respect to the corresponding target gene, in particular as defined above , In addition, the target for a therapeutic approach can also be seen in the (poly) peptide encoded by the depression-inducing or depression-associated gene.

Yet another subject of the present invention - according to one aspect of the present invention - is the use according to the invention according to claim 15, d. H. in other words, the use of an inhibitor and / or repressor of a (poly) peptide encoded by a depression-inducing and / or depression-associated nucleic acid molecule, in particular gene and / or its DNA sequence and / or its associated RNA sequence, for the production a drug or medical device for the prophylactic and / or curative treatment of depression.

Also in this regard, an identified test substance can be used as inhibitor or repressor in the previously described method.

Yet another subject of the present invention - according to an aspect of the present invention - is the use according to the invention according to claim 17, d. H. in other words, the use of at least one substance for the manufacture of a medicament or medicament for the prophylactic and / or curative treatment of depression, which substance regulates, in particular reduces, or at least inhibits, the gene activity and / or gene expression of at least one depression-inducing and / or depression-inducing gene.

Thus, the targeted adjustment or regulation or reduction of gene activity, the depression can be specifically suppressed. The emergence of depression, especially the interferon-induced depression but also the endogenous depression, is thus - as the applicant has found completely surprising - associated with increased gene activity of the depression-inducing or depression-associated gene.

According to a preferred embodiment of the invention, the substance can interact with the promoter and / or enhancer of the depression-inducing and / or associated gene and / or interact in such a way that the binding of in particular endogenous transcription factors, in particular activators, to the promoter and / or enhancer is prevented or at least inhibited.

Equally, however, it is also possible that the substance interacts with a particular endogenous transcription factor, in particular activator, in such a way that the binding of the transcription factor, in particular activator, to the promoter and / or enhancer of the depression-inducing and / or depression-inducing gene is prevented or at least inhibited ,

Equally, however, it is also possible for the substance to react with the endogenous transcriptional activators themselves, thereby causing inactivation of the transcriptional activator per se, in order to reduce gene activity in this way.

The substance used in the context of the use according to the invention may be a substance identified according to the above-described method of the invention.

For further details with respect to the use according to the invention in accordance with the sixth, seventh and eighth aspects of the present invention, reference may be made to the other embodiments with regard to the other aforementioned aspects of the present invention, which apply mutatis mutandis in this context.

Yet another object of the present invention - according to a ninth aspect of the present invention - is the inventive method according to claim 20, ie in other words a method for determining the risk of a subject to develop depression and / or for the prediction of individual drug effects , and / or side effects, in particular depression as a result of interferon therapy, whereby the subject is assigned an increased risk of disease and / or the subject is assigned altered drug effects and / or side effects in the event that the subject has an increased risk of gene activity and / or gene expression of at least one depression-inducing and / or depression-associated gene.

The method according to the invention can be carried out, for example, by means of an expression profile, in particular in the context of an interferon therapy, wherein the expression profile can be adjusted, for example, with a control group not treated with interferon or with an interferon-treated control group whose subjects do not develop depression and if an increased gene activity with regard to the previously defined depression-inducing or depression-associated genes is associated, for example, an increased risk of disease for the affected subject. As regards the statement on altered drug effects or side effects, for example, these may specifically refer to the interferon used in the treatment of type C hepatitis. Thus, for example, the pharmacological substance, in particular interferon, can be said to have an increased side effect with regard to the respective subject in the case of a detected increased gene activity of the depression-inducing or depression-associated genes in question, in particular with regard to the development of depression.

Accordingly, in the context of the method according to this aspect of the present invention, the medicament is in particular α-interferon administered in the context of the treatment or therapy of hepatitis, in particular chronic hepatitis type C, in particular pegylated α-interferon, its side effects can be determined in relation to the development of depression. In this way, the success of a treatment approach in the context of interferon administration in type C hepatitis can be better estimated.

Finally, another object of the present invention - according to a tenth aspect of the present invention - is the inventive method according to claim 22, ie in other words a method for the identification and / or determination of at least one depres- sion inducing and / or depressionsassoziierten nucleic acid molecule, in particular one Gene, preferably one in connection with the delivery of interferon-related depression-inducing and / or depression-associated gene, the method comprising the following steps: (a) generating a gene expression and / or gene activity profile from a plurality of probands of a subject group each treated with interferon;

(b) analysis and comparison or comparison of the respective gene expression and / or gene activity profiles of (i) as a result of interferon therapy

On the one hand, and on the other hand, (ii) volunteers who did not suffer from depression as a result of interferon therapy fell ill with depression

(c) identification of at least one nucleic acid molecule, in particular of at least one gene, which in (i) is suffering from depression

Subjects show increased gene expression and / or gene activity compared to (ii) non-depression subjects.

The method may comprise the following step subsequent to step (c):

(d) assignment of the nucleic acid molecule, in particular gene, identified in step (c) as a depression-inducing and / or depression-associated nucleic acid molecule, in particular depression-inducing and / or depression-associated gene, preferably as depression-inducing and / or depression-associated with the administration of interferon Gene.

The method according to the invention in accordance with this aspect of the present invention can be used for example by means of differential expression using so-called DNA chips. In this case, it is possible to proceed in such a way, for example, that RNA is first isolated from the blood of a test subject and this isolate is applied to specific gene chips and the expression level for certain genes is determined in the context of evaluation or analysis methods known to the person skilled in the art with an increased level of expression the properties of a depression-inducing or depression-associated gene are attributed the. For further explanations in this regard with regard to the specific procedure, reference may be made to the exemplary embodiments.

In this way it is possible to identify further genes which are associated with or cause, in particular, depression induced by the use of interferon or in connection with endogenous depression.

Particularly in the case where the disease is an endogenous depression, the method for identifying and / or determining at least one depression-inducing and / or depression-associated nucleic acid molecule, in particular a gene, may comprise the following steps: (a) Generation of a gene expression and / or gene activity profile of a large number of test persons of a group of probands who are each suffering from endogenous depression;

(b) Analysis and comparison or comparison of the respective gene expression and / or gene activity profiles of (i) subjects suffering from endogenous depression on the one hand and (ii) subjects not suffering from endogenous depression on the other hand and

(c) Identification of at least one nucleic acid molecule, in particular of at least one gene, which exhibits increased gene expression and / or gene activity in (i) the subjects suffering from endogenous depression in comparison to (ii) the subjects not suffering from endogenous depression.

The method may comprise the following step subsequent to step (c):

(d) assignment of the nucleic acid molecule, in particular gene, identified in step (c) as a depression-inducing and / or depression -associated nucleic acid molecule, in particular depression-inducing and / or depression-associated gene, preferably as a gene associated with endogenous depression. With regard to the method according to the invention according to this and the ninth aspect of the present invention, reference may be made to the remaining embodiments with regard to the further objects of the present invention, which apply accordingly.

As indicated above, the identified genes are, in particular, depression-inducing or depression-associated genes and / or IFN-response genes whose expression correlates with IFN-induced depression, preferably depression-inducing or depression-associated genes. In this regard, in the context of the present invention, in particular genes are used which are selected from the group of

DYNLT1, in particular with the transcript ID (locus) NM 006519, in particular according to SEQUENCE LISTING SEQ. ID. NO. 1 and / or Table 1,

MEF2A, in particular with the transcript ID (locus) NM 005587, in particular according to SEQUENCE LISTING SEQ. ID. NO. 2 and / or Table 1,

TORIB, in particular with the transcript ID (locus) NM 014506, in particular according to SEQUENCE LISTING SEQ. ID. NO. 3 and / or Table 1, - DISCl, in particular with the transcript ID (locus) NM O 18662, in particular according to SEQUENCE LISTING SEQ. ID. NO. 4 and / or Table 1,

GCH1, in particular with the transcript ID (locus) NM_000161, in particular according to SEQUENCE LISTING SEQ. ID. NO. 5 and / or Table 1,

ST3GAL5, in particular with the transcript ID (locus) NM_003896, in particular according to SEQUENCE LISTING SEQ. ID. NO. 6 and / or Table 1,

- PSMB9, in particular with the transcript ID (locus) NM 002800, in particular according to SEQUENCE LISTING SEQ. ID. NO. 7 and / or Table 1, - GLRX, in particular with the transcript ID (locus) NM_002064, in particular according to SEQUENCE LISTING SEQ. ID. NO. 8 and / or Table 1, - RBCKl, in particular with the transcript ID (locus) NM 006462, in particular according to SEQUENCE LISTING SEQ. ID. NO. 9 and / or Table 1, and

- ZNF200, in particular with the transcript ID (locus) NM 003454, in particular according to SEQUENCE LISTING SEQ. ID. NO. 10 and / or Table 1,

STAT1, in particular with the transcript ID (locus) NM 007315, in particular according to SEQUENCE LISTING SEQ. ID. NO. 1 1 and / or Table Ie 2,

RTP4, in particular with the transcript ID (locus) NM_022147, in particular according to SEQUENCE LISTING SEQ. ID. NO. 12 and / or Table 2,

UBE2L6, in particular with the transcript ID (locus) NM 004223, in particular according to SEQUENCE LISTING SEQ. ID. NO. 13 and / or Table 2, - GBPl, in particular with the transcript ID (locus) NM 002053, in particular according to SEQUENCE LISTING SEQ. ID. NO. 14 and / or Table 2,

CCL8, in particular with the transcript ID (locus) NM 005623, in particular according to SEQUENCE LISTING SEQ. ID. NO. 15 and / or Table 2,

TNFSF10, in particular with the transcript ID (locus) NM_OO381O, in particular according to SEQUENCE LISTING SEQ. ID. NO. 16 and / or Table 2, as well as their combinations.

In the context of the present invention, depression-inducing or depression-associated genes are preferably used according to the invention, the gene or genes being selected from the group of DYNLT1, in particular with the transcript ID (locus) NM_006519, in particular according to SEQUENCE LISTING SEQ. ID. NO. 1 and / or Table 1, - MEF2A, in particular with the transcript ID (locus) NM 005587, in particular according to SEQUENCE LISTING SEQ. ID. NO. 2 and / or Table 1,

TORIB, in particular with the transcript ID (locus) NM O 14506, in particular according to SEQUENCE LISTING SEQ. ID. NO. 3 and / or Table 1,

DISCl, in particular with the transcript ID (locus) NM 0 18662, in particular according to SEQUENCE LISTING SEQ. ID. NO. 4 and / or Table Ie 1,

ST3GAL5, in particular with the transcript ID (locus) NM 003896, in particular according to SEQUENCE LISTING SEQ. ID. NO. 6 and / or Table 1, - PSMB9, in particular with the transcript ID (locus) NM 002800, in particular according to SEQUENCE LISTING SEQ. ID. NO. 7 and / or Table 1,

- GLRX, in particular with the transcript ID (locus) NM 002064, in particular according to SEQUENCE LISTING SEQ. ID. NO. 8 and / or Table 1,

RBCK1, in particular with the transcript ID (locus) NM_006462, in particular according to SEQUENCE LISTING SEQ. ID. NO. 9 and / or Table l, and

- ZNF200, in particular with the transcript ID (locus) NM 003454, in particular according to SEQUENCE LISTING SEQ. ID. NO. 10 and / or Table 1, as well as their combinations. Particularly preferred according to the invention in the context of the present invention are depression-inducing or depression-associated genes, the gene or genes being selected from the group of DYNLT1, MEF2A, TORIB, DISC1, GCH1 and ST3GAL5, in particular as defined above.

According to a less preferred embodiment of the present invention, in particular IFN response genes whose expression correlates with IFN-induced depression are used in the context of the present invention, the gene or genes being selected from the group of

RTP4, in particular with the transcript ID (locus) NM 022147, in particular according to SEQUENCE LISTING SEQ. ID. NO. 12 and / or Table 2, - UBE2L6, in particular with the transcript ID (locus) NM 004223, in particular according to SEQUENCE LISTING SEQ. ID. NO. 13 and / or Table 2,

- GBPl, in particular with the transcript ID (locus) NM 002053, in particular according to SEQUENCE LISTING SEQ. ID. NO. 14 and / or Table 2,

CCL8, in particular with the transcript ID (locus) NM_005623, in particular according to SEQUENCE LISTING SEQ. ID. NO. 15 and / or Table Ie 2,

TNFSF10, in particular with the transcript ID (locus) NM 003810, in particular according to SEQUENCE LISTING SEQ. ID. NO. 16 and / or Table 2, as well as their combinations.

Furthermore, the depression is, in particular, a depression which is associated with the treatment and / or therapy of hepatitis, in particular chronic type C hepatitis. In particular, depression is one such disease associated with and / or caused by α-interferon, in particular pegylated α-interferon, in particular wherein depression is due to a preferably systemic application of α-interferon, in particular pegylated α-interferon, in particular in the context of the treatment and / or therapy of hepatitis, in particular chronic hepatitis type C, is and / or is caused thereby.

In other words, the depression is a disease which is associated with an increased gene activity and / or gene expression of at least one gene as previously defined and / or caused thereby, in particular wherein the gene activation by a preferably systemic application of α- Interferon, in particular pegylated α-interferon, in particular in the context of the treatment and / or therapy of hepatitis, especially chronic hepatitis type C, is related and / or caused thereby.

As indicated above, however, the depression in question may also be an endogenous depression in the context of the present invention.

Furthermore, the applicant has also found, moreover, completely surprising that in the case of endogenous depression in the affected patients also an increased interferon level or an increased interferon concentration and / or increased interferon production may be present. In this connection, the Applicant has been able to show by means of studies that in patients with endogenous depression an increased level or an increased concentration and / or an increased production or (bio-) synthesis of endogenous interferon, in particular α-interferon (IFN-α ), such as α-1-interferon (IFN-α-1) and / or α-2-interferon (IFN-α-2), β-interferon (IFN-β) and / or γ-interferon (IFN-γ) , as shown in the embodiments. The Applicant has surprisingly found that the occurrence of endogenous depression, in particular associated with a severe depressive episode (SDE), also by an increased level or concentration and / or increased production of endogenous interferon, in particular of the aforementioned kind , can be caused. In this regard - without wishing to be bound by theory - the occurrence of an endogenous depression, which correlates with the presence of an increased level or an increased concentration and / or production of endogenous interferon, in particular of the aforementioned type, can be explained by: The increased interferon level or the increased concentration and / or production of endogenous interferon sometimes causes increased gene activity, in particular of depression-inducing or depression-associated genes, for example as mentioned above.

Accordingly, a further object of the present invention is the discovery and / or the provision of substances which the physiological activity of endogenous interferon, in particular α-interferon, such as α-1-interferon and / or α-2-interferon, ß-interferon and / or γ-interferon, modulate, in particular prevent or at least reduce. Such substances can be used as a therapeutic in the context of a prophylactic and / or curative treatment of endogenous depression. This may be, for example, a substance which reduces or inhibits the production or (bio) synthesis of interferon, in particular of the aforementioned type. The substance inhibiting or reducing the production or (bio-) synthesis of interferon may be such that the substance intervenes in the interferon synthesis pathway or regulates it or interacts with components of the interferon synthesis pathway, so that in this way the endogenous pathways are interpenetrated Formation of interferon, in particular of the aforementioned type, suppressed or at least reduced. In this regard, it may, for example, also be a gene-regulating substance which, in particular, modulates, in particular reduces, the gene activity of genes involved in the (B 1o) synthesis of interferon. Likewise, this subject matter of the present invention also encompasses the discovery or provision of substances which modulate, in particular prevent, the interferon signaling pathway. In this context, the substance z. B. with endogenous interferon, in particular α-interferon, such as IFN-α-1 and / or IFN-α-2, IFN-ß and / or IFN-γ, even interact in particular such that the activity of interferon is reduced or is inhibited. Thus, for example, the substances may be an interferon blocker. For example, the substances may also be such a compound which, for example, with Interferon receptors interact, for example in the manner of an interferon receptor ocher.

The present invention also relates to the use of the above-described substances which modulate the activity of endogenous interferon, in particular α-interferon, such as IFN-α-1 and / or IFN-α-2, IFN-β and / or IFN-γ , in particular inhibit, for the manufacture of a medicament for the prophylactic and / or curative treatment of endogenous depression.

In addition, the present invention equally relates to a method for determining the risk of a subject suffering from endogenous depression, wherein the subject is associated with an increased risk of endogenous depression in the event that the test person an increased endogenous interferon or ., an increased concentration of endogenous interferon and / or increased production of interferon, in particular α-interferon, such as IFN-α-1 and / or IFN-α-2, IFN-ß and / or IFN-γ has.

In the context of the present invention, overall, it has been possible to provide a new approach for the treatment of depression, in particular of the previously defined type, which starts on a genetic basis. In the context of the present invention, in a completely surprising manner, it has been possible to identify genes which cause depression, in particular in patients who are treated with α-interferon, and thus represent an excellent target for the treatment or prevention of depression.

On this basis, both possibilities for the early detection of depression as well as for the treatment of depression are provided in the context of the present invention, wherein the depression can be in particular an interferon-mediated depression, but also an endogenous depression. As stated above, further depression-inducing or depression-associated genes can be identified with the aid of the method according to the invention. The genes identified in this way contribute to the development of depression, especially in patients, who are treated with interferon, to predict or avoid at baseline. This is of tremendous importance as approximately 30% of interferon-treated patients develop depression. In addition, the identified depression-inducing or depression-associated genes can play a role in the pathogenesis of endogenous depression, so that according to the invention a targeted pharmacological suppression of their activity can take place

Further embodiments, modifications, variations and advantages of the present invention will be readily apparent to and can be realized by those skilled in the art upon reading the description, without thereby departing from the scope of the present invention.

The present invention will be illustrated by the following embodiments, which by no means limit the present invention.

EMBODIMENTS;

I. Investigations on patients with hepatitis C: Based on the following studies, it is possible to identify relevant risk factors for IFN-induced depression for the development of preventive treatment strategies. In patients with hepatitis C, the primary transcriptional response to IFNα-2a plus ribavirin was investigated. Candidate genes whose expression is associated with IFN-induced major depression can be identified.

Patients and Methods: A total of 50 Caucasian patients with histologically confirmed chronic hepatitis C were treated with standard combination therapy consisting of pegylated α-interferon IFNα-2a (Pegasys, 180μg once weekly) for 12 months (HCV genotype 1, n = 40) or 6 months (HCV genotype 2/3, n-3/7) in combination with ribavirin (800-1200 mg daily). RNA was isolated from peripheral blood (PAXgen, PreAnalytiX) taken 12 hours before and 12 hours after the first injection. Gene expression profiles of approximately 22,000 human genes were determined using DNA chips (HG-Ul 33A 2.0, Affymetrix). After normalization of the raw chip data, genes were determined by means of significance and class prediction analyzes, which are differentially regulated in patients with and without IFN / IFNα-induced depression. Expression of these genes was validated by quantitative real-time RT-PCR. Psychologically, the patients were examined in cooperation with the Rheinische Kliniken Essen, Department of Psychosomatic Medicine and Psychotherapy. By means of mini-DIPS (diagnostic interview for mental disorders) and psychometric instruments, such as the Beck Depression Inventory, the severity of an IFN-induced depression was analyzed qualitatively and quantitatively on a quarterly basis.

Results:

1 out of 50 patients (22%) suffered from IFN-induced depression. 1 1 randomly selected non-depressive patients were included in a comparative analysis. As a result of the class prediction analysis, an IFN induced depression with the help of 16 genes with an accuracy of 91% predictable. Of these genes, 6 represent typical IFN-stimulated genes (ISG) or IFN response genes. Out of these 16 genes, there were 6 genes in which an association with repeated severe depressions or neuronal development processes in the brain has already been published ( "depression Gene"). Transcriptional response to IFN was more pronounced in all 16 genes in patients with IFN-induced depression than in the control group with no clinical depression. Thus, the gene response in patients with IFN-induced depression is always stronger than in the comparison group. The basal expression (before IFN injection) of the IFN response genes is for the most part significantly decreased in patients with IFN-induced depression. The basal expression of the 6 "depression genes" showed no significant differences in both groups. These results could be confirmed by quantitative RT-PCR (real-time polymerase chain reaction).

Conclusions:

The data indicate causative involvement of interferon response genes in the development of severe depression, which is a frequent adverse event in antiviral therapy with IFN-α. Differences in the response behavior of these genes allow predictions regarding the manifestation of major depression already in the initial phase of therapy. Functional analysis of the identified genes could allow the development of new drugs for improved tolerability and thus improved HCV therapy efficiency. In addition, the genes we identify may also be important for the pathogenesis and thus the treatment of endogenous, not primarily IFN-associated depression.

Detailed description of the methods:

1. Sampling and Isolation of Total RNA:

From each patient, after his written consent in the course of routine examinations, about 10 ml of arm vein blood was taken 12 hours before and 12 hours after the first IFNα injection. to

Stabilization of RNAs in the peripheral blood cells directly in the blood PAXgene Blood RNA Tubes (PreAnalytiX, Becton Dickinson, Heidelberg) were used. Thereafter, the RNA was prepared using the PAXgene Blood RNA Kit (PreAnalytiX, Qiagen, Hilden) according to the manufacturer's instructions. Briefly: The PAXgene tubes are centrifuged (10 min, 4000 U / min, 20 ⁰ C), the supernatant aspirated, the pellet resuspended in 5 ml RNase-free water (Kit). After renewed centrifugation (10 min, 4000 rev / min, 20 ⁰ C), the supernatant is filtered off with suction and discarded. The pellet is resuspended in 360 μl of Buffer BRI (Kit) and transferred to a RNase-free 1.5 ml tube (Kit). After adding 300 μl of buffer BR2 (kit) and 40 μl of proteinase K (kit), the sample is mixed and incubated for 15 min at 55 ° C (heating block). Subsequently the lysate (approximately 700 ul) is set to the "shredder" column (Kit) loaded and centrifuged (3 min, 13.000 rev / min, 20 ⁰ C). The supernatant is transferred to a new RNase-free 1.5 ml tube (kit) and 360 μl of ethanol (abs.) Are pipetted in and the sample is mixed. A PAXgen column per sample is loaded with 700 ul of the lysate and centrifuged (1 min, 10,000 U / min, 20 ⁰ C). The flow and collection tubes are discarded, the column placed in a new collection tube (kit), loaded with the remainder of the sample and recentrifuged (1 min, 10,000 rpm, 20 ^° C.). The flow and collection tubes are discarded, the column placed in a new collection tube (kit), washed sequentially once with buffer BR3 (kit) and twice with buffer BR4 (kit). Thereafter, the flow and collection tubes are discarded, the column placed in an elution tube (kit) and washed with 45 μl of buffer BR5 (Kit). The eluate is again loaded onto the column and centrifuged (1 min, 10,000 U / min, 20 ⁰ C). Four samples of one patient per collection time are pooled (about 180μl).

The RNA is further concentrated for the subsequent chip analyzes with the RNeasy MinElute Cleanup Kit (Qiagen, Hilden). In brief: samples are adjusted to 200 μl with RNase-free water. Then 700 μl buffer RLT (Kit) and 500 μl ethanol (abs.) Are pipetted into it. One column per sample is loaded with 700 μl of sample and centrifuged (15 s, 10,000 rpm, 20 ^° C.). Then it is washed with 500 μl buffer RPE (Kit). Then 500 .mu.l ethanol (80%) are pipetted and centrifuged (2 min, 10,000 rev / min, 20 ⁰ C). Discard the flow and collection tubes, place the column in a new collection tube (kit), centrifuge the column with the lid open. fuged and dried (5 min, 13,000 rpm, 20 ^° C.). And collecting tube flow are discarded, the column put in a Elutionsröhrchen (Kit) with 18 .mu.l buffer BR5 (kit) washed (1 min, 13,000 U / min, 20 ⁰ C). Incubating the sample for 5 min then at 65 ° C (heat block) cooling on ice and stored at -80 ⁰ C.

2. Analysis of Gene Expression Using Affvmetrix GenChips (Oligonucleotide

Microarray): The expression analyzes on Affymetrix GenChips were carried out in cooperation with the local BioChip Laboratory (Institute of Cell Biology, University Hospital Essen). First, the total RNA was converted into double-stranded cDNA. For the synthesis of the first cDNA strand, 8 μl (10 μg) of total RNA were added to each sample together with 1 μl of a mixture of 3 poly A control RNAs and 1 μl (100 μM) of T7-oligo-d (T) 24 primer (MWG Biotech, Munich) for 10 min at 70 ⁰ C (heating block) and then transferred to ice. By DTT and 1 .mu.l (10 mM) dNTP mix was added 4 ul "First-beach" buffer (5x), 2 .mu.l (1 M 0) are pipetted and incubated for 2 min at 42 ⁰ C (heat block). Thereafter, 2 μl (200 units) of Superscript II (Life Technologies, Karlsruhe) were added thereto and the batch was incubated for 1 hour at 42 ° C.

For the synthesis of the second cDNA strand, the following batch was pipetted: 30 μl of "second strand" buffer (5 ×), 91 μl of RNase-free water, 3 μl (10 mM) of dNTP mix, 4 μl (40 units) of Escherichia coli DNA polymerase I (Life Technologies), 1 μl (12 units) of E. coli DNA ligase (TaKaRa, Gennevilliers, France) and 1 μl (2 units) of RNase H (TaKaRa). This reaction mixture is incubated for 2 hours at 16 ° C (coolable thermoblock). Subsequently, 2.5 μl (10 units) of T4 DNA polymerase I (TaKaRa) was added, followed by incubation for 5 min at 16 ° C. Finally, the reaction was stopped by the addition of 10 μl (0.5 M) of EDTA and the double-stranded cDNA extracted with phenol / chloroform. The aqueous phase was separated (phase-lock gel separation, Eppendorf, Hamburg). After precipitation, the cDNA was dissolved in 12 μl of RNase-free water. The synthesis of the biotinylated cRNA was carried out with the "Bio-Array High Yield RNA Transcript Labeling Kit" (Enzo Diagnostics, NY, USA) according to the manufacturer. The labeled cRNA was purified with the RNeasy Mini Kit (Qiagen). The fragmentation of the cRNA, the hybrids The GeneArray Scanner 2500 (Agilent, Paolo Alto, USA) was screened, washed, stained and scanned (HG-U 133 A 2.0, Affymetrix, Santa Clara, USA) according to the manufacturer's instructions (Technical Manual, Affymetrix). carried out.

3. Analysis of GenChip data:

The processing of the scanner images, the calculation of the signals and the comparative analyzes of the sample pairs (before and after IFN injection) were carried out with the GeneChip Operating Software (GCOS vi .2, Affymetrix) using the MAS5 algorithm. Further analysis and filtering of the data was carried out using the Data Mining Tool v3.1 (Affymetrix). The evaluation of the raw data with GCOS provided in the single-chip analysis for each gene a so-called "detection call", an evaluation of the sample, whether the respective gene is active (P = present) or inactive (A = absent). In the comparative chip analysis, the data from the sample after IFN injection was compared to the corresponding data from the same patient before IFN injection (baseline). After these comparative analyzes, GCOS calculated the so-called "Change CaIl", an evaluation of the sample, whether the respective gene after IFN injection increased (I = increased), decreased (D = decreased) or unchanged (NC = not changed). In order to reduce the amount of data to a reasonable level, initially only genes were filtered out which were elevated (I-Call) or decreased (D-CallI) in at least one patient. Of 22,216 genes remained after 8,093 genes left. Further gene groups were used in the further statistical analyzes: a) I- or D-calcium in more than one patient (4,236 genes), b) I- or D-calcium in more than 25% of the patients (1,342 genes) and c) I- or D-calcium in more than 50% of patients (586 genes).

To minimize individual experimental variations, the data of all GenChips were normalized by the RMA method (RMA = Robust Multiarray Average). For this purpose, a background adaptation and a quantile normalization of the chip raw data was carried out with the RMAExpress v. 4.1 (http://rmaexpress.bmbolstad.com). Further analyzes were done by spreadsheet (Excel 2003, Microsoft). Identification of candidate genes that regulate differentially in the two clinical groups of patients with and without IFN-induced depression 2-class analyzes were performed. On the one hand, significantly different genes were identified with the Excel add-in SAM v3.0 (SAM = Significance Analysis of Microarrays, http://www.stat.stanford.edu/~tibs/SAM). On the other hand, with the Excel add-in PAM v2.1 (Prediction Analysis of Microarrays, http://www.stat.stanford.edu/~tibs/PAM) it was examined whether a prediction of belonging to one of the two clinical groups is possible and how many genes are necessary for it. For additional statistical analysis (Correlation, Wilcoxon Test, ANOVA) and graphics, GraphPad Prism v4.03 (GraphPad Software, San Diego, USA) was used.

4. Validation of the Expression Data by Quantitative RT-PCR:

To check the gene expression data from the GenChip experiments, the mRNA of individual candidate genes was determined before or after the IFN injection by means of quantitative "real-time PCR" (PCR = polymerase chain reaction). Up to 36 reaction tubes (0.2 μl, NerbePlus, Winsen / Luhe) were measured in the Rotor-Gene 2000 Real-Time Amplification System (Corbett Research, Mortlake, Australia). The transcription of the RNA into cDNA and the subsequent amplification (including real-time detection) was carried out as a quantitative one-step reverse transcriptase PCR (qRT-PCR) using the QuantiTect SYBR Green RT-PCR Kit (Qiagen) according to the manufacturer , Briefly, 2 μl (20-200 ng) of each RNA sample were pipetted to 23 μl RT-PCR mix consisting of 12.5 μl RT master mix, 0.3 μl RT mix, 7.7 μl RNase-free Water and 2.5 μl (0.5 μM) primer (QuantiTect Primer Assay, Qiagen). In the Rotor-Gene 2000, the samples were first blocked for 30 min at 5O ⁰ C incubated (cDNA reaction), followed by 15 min at 95 ° C (inactivation of reverse transcriptase, activation of the Hot Start Taq polymerase). The samples were amplified by 35 to 40 cycles with 20 sec at 95 ° C, 20 sec at 55 ⁰ C and 40 sec at 72 ° C. To assess the specificity of the reaction, a melting curve was taken after the last cycle. The temperature of 72 to 94 ° C was gradually increased by 0.5 ⁰ C with a fluorescence measurement (510 nm wavelength) after each temperature step. During amplification, the fluorescence measurement was performed after each cycle, at the end of the 72 ° C phase. In each PCR run negative controls (RNase-free water instead of RNA) were carried along with the patient samples for each primer pair used. For each PCR approach, the number of mRNA copies was calculated using standard curves. To account for differences in the starting concentration of RNA, for each RNA sample, the mRNA concentration was determined for β-actin, a housekeeping gene which is constantly expressed under IFNα stimulation.

Table 1:

Depression-inducing or depression-associated genes:

Table 2;

IFN response genes or IFN-stimulated genes (ISG) whose expression correlates with IFN-induced depression:

II. Investigations on psychiatric patients and comparison to patients with hepatitis C;

To validate depression-associated genes, 23 psychiatric patients receiving in-patient treatment for a major depressive episode (SDE) were prospectively studied (Table 3). All patients received antidepressant medication at the time of molecular biology examinations. The diagnosis of an SDE was based on a psychiatric evaluation by a specialist in psychiatry. The severity of depression was determined using the Hamilton Depression Rating Scale (HAMD-17). Recurrent depressive disorder (ICD-10: F33.2) was diagnosed in 18 patients, with one of these patients simultaneously showing psychotic symptoms (ICD-10: F33.3). Three patients had bipolar affective disorder with a major depressive episode (ICD-10: F31.4) and two patients had a major depressive episode (ICD-10: F32.2). Eleven healthy subjects without clinical signs of depressive moods served as controls.

Peripheral blood (PBMC) was collected from healthy volunteers and psychiatric patients and stimulated in vitro with 100 U / ml of pegylated IFN-α-2a for 16 hours. Then expression of ISGs as well as selected genes was determined before or after stimulation.

For this purpose, the following additional methods were used:

1. RNA isolation from cultured PBMC:

Total RNA was isolated from cells by Trizol (Invitrogen, Karlsruhe, Germany). This was purified by DNase digestion of residual genomic DNA using RNeasy Mini Kit and RNase-Free DNase Set (both Qiagen).

2. Real-Time Detection of IFNGen Transcripts by One-Step RT-PCR: One-step RT-PCR (one-step RT-PCR with real-time detection was performed with the Rotor-Gene 2,000 real-time Amplification system (Corbett Research, Mortlake, Australia) and the QuantiTect SYBR Green RT-PCR Kit (Qiagen, Hilden, Germany). For each mRNA, the copy numbers were related to the number of β-actin transcripts. 3. Isolation and in vitro stimulation of PBMC:

PBMC were isolated from heparinized blood by centrifugation on a collin density gradient (Lymphocyte Separation Medium 1077, PAA, Coelbe) at 350g for 20 min. The cells were transferred to 6-well plates (Greiner, Nürtingen) in a concentration of 2x10 ⁶ cells / well and in medium (RPMI 1640, PAA) containing 2% pooled human AB serum, 2 mM L-glutamine and 50 μg / ml. ml gentamicin, cultured at 37 ⁰ C and 5% CO ₂ . A medium control without stimulus was included in all experiments.

Results:

In patients with SDE, pegylated IFN-α-2a led to a significantly higher induction of the target genes GCH1, TOR1B, DYNLT1, DISC1 and a higher induction of MEF2A and ST3GAL5. No difference was found with conventional ISGs such as MXI or ISG 15 (Figure 7D) as well as IFITI and IFI 16 (not shown). It is concluded that in patients with SDE there is a selective and not a general overstimulation by Type I interferons.

In this regard, FIGS. 7A to 7D show the IFN-stimulated expression of genes in patients with HCV on the one hand and psychiatric patients with an SDE on the other hand. In this regard, total RNA was isolated from HCV patients with (n = 1 1) or no (n = 11) consecutive IFN-induced depression twelve hours before and twelve hours after the first injection of pegylated IFN-α-2a. To validate this data in an independent cohort, PBMC were isolated from eleven healthy controls and 22 patients with SDE and stimulated with 100 U / ml of pegylated IFN-α-2a in vitro for 16 hours. Gene expression was analyzed by quantitative RT-PCR. The data are shown as box plots (Range, 25% and 75% percentile, mean).

Analysis of gene expression without prior IFN stimulation in patients with SDE showed significant upregulation of conventional ISGs such as STAT1 and IFIT1 compared to healthy controls (Figure 8A), which could be due to increased production of endogenous IFNs in these patients. To test this hypothesis, the basal values of the most common IFN-α subtypes (IFN-α-1 and IFN-α-2), IFN-β and IFN-γ were analyzed by means of quantitative RT-PCR determined (Figure 8B). There was a marked upregulation of IFN-ß production in SDE patients compared to normal controls. Furthermore, there was an increased production of IFN-α-1 and IFN-α-2 as well as a trend towards a higher production of IFN-γ.

In this regard, Figures 8A and 8B show increased gene expression and IFN production in psychiatric patients with SDE. In this regard, total RNA was isolated from HCV patients with (n = 1 1) or without (n = 1 1) consecutive IFN-induced depression, eleven healthy controls and 22 patients with SDE. Basal gene expression (Figure 8A), expression of IFN-α-1, -α-2 (both Figure 8B, supra), IFN-β and IFN-γ (both Figure 8B, bottom) was assayed by quantitative RT -PCR analyzed. The data are shown as box plots (Range, 25% and 75% percentiles, mean).

Table 3:

patient information

1 shows the results of gene chip analyzes for the expression of depression-inducing or depression-associated genes in hepatitis type C patients with Pegasys therapy.

2 shows the results of GenChip analyzes for the expression of depression-inducing or depression-associated genes in patients with type C hepatitis with or without interferon-induced depression.

FIG. 3 shows GenChip data for the expression of further depression-inducing or depression-associated genes in hepatitis type C patients with Pegasys therapy.

4 shows GenChip data for the expression of further depression-inducing or depression-associated genes in hepatitis C type.

Patients with or without IFN-induced depression.

5 shows the results of GenChip analyzes for the expression of IFN response genes whose expression correlates with IFN-induced depression in hepatitis type C patients with Pegasys

Therapy.

Figure 6 shows the results of GenChip analyzes for expression of IFN response genes whose expression correlates with IFN-induced depression in patients with type C hepatitis with or without interferon-induced depression.

Figure 7A shows gene expression of GCHI and TORIB in patients with hepatitis C virus (HCV) and psychiatric patients with a major depressive episode (SDE) and comparison to control groups.

Figure 7B shows the gene expression of DYNLT1 and DISC1 in patients with HCV and psychiatric patients with SDE and comparison to control groups. Figure 7C shows gene expression of MEF2A and ST3GAL5 in patients with HCV and psychiatric patients with SDE and comparison to control groups.

Figure 7D shows gene expression of MXI and ISG 15 in patients with HCV and psychiatric patients with SDE and comparison to control groups.

Figure 8A shows gene expression of STAT1, IFIT1, ISG15 and MX1 in psychiatric patients with SDE.

Figure 8B shows IFN production in different patient groups.

In the figure representations, the abbreviations n and N = normal, D = depressive, HCV = hepatitis C virus infection, SDE = severe depressive episode, n.s. = not significant, Ko = control, HCV / D = hepatitis C virus infection, depressive.

Claims

claims:

1. Use of at least one depression-inducing and / or depression-associated nucleic acid molecule, in particular gene and / or its DNA sequence and / or its associated RNA

Sequence, and / or at least one (poly) peptide encoded by the nucleic acid for the discovery and / or provision of a diagnostic agent for the detection of depression and / or a drug for the prophylactic and / or curative treatment of depression and / or to determine the Risk of developing depression and / or

Prediction of individual drug effects and / or drug side effects.

2. A method for identifying an inhibitor and / or repressor of a depression-inducing and / or depression-associated nucleic acid molecule, in particular a gene and / or its DNA sequence and / or its associated RNA sequence, comprising the following steps:

(A) contacting the nucleic acid molecule with at least one test substance under conditions which allow an interaction, in particular binding, of the test substance (s) to the nucleic acid molecule; and

(b) detecting and / or analyzing whether the test substance (s) limit or prevent the gene activity and / or expression of the nucleic acid molecule and / or whether the test substance (s) limit or prevent the depression-inducing and / or depression-associated properties of the nucleic acid molecule.

3. Method for identifying an inhibitor and / or repressor of a (poly) peptide encoded by a depression-inducing and / or depression-associated nucleic acid molecule, in particular gene and / or its DNA sequence and / or its associated RNA sequence, comprising the following steps : (a) contacting the (poly) peptide with at least one test substance under conditions which allow an interaction, in particular binding, of the test substance (s) to the (poly) peptide; and (b) detecting and / or analyzing whether the test substance (s) limit or prevent the depression-inducing and / or depression-associated properties of the (poly) peptide.

4. The method according to claim 2 or 3, wherein a plurality of test substances are used and the following steps are carried out:

(A) testing of various test substances in different reaction vessels, wherein those test substances which do not limit or prevent the depression-inducing and / or depression-associated properties of the nucleic acid molecule and / or the (poly) peptide are no longer taken into account in the further test procedure;

(b) distribution of test substances from such reaction vessels in which a reduction or elimination of depression-inducing and / or depression-associated properties of the nucleic acid molecule and / or the (poly) peptide in step (a) has been determined, to new reaction vessels and repetition of Step (a) with the new reaction vessels; and

(c) repeating step (b) until a single test substance is identified to which the reduction or inhibition of depression-inducing and / or depression-associated properties of the nucleic acid molecule and / or the (poly) peptide can be assigned.

5. The method according to any one of claims 2 to 4, wherein the test substance (s), the nucleic acid molecule and / or the (poly) peptide are coupled to a readout system (readout system) and / or wherein a readout system is added to the test batch is and / or wherein the readout system after binding of the test substance (s) with the nucleic acid molecule and / or the (poly) peptide provides a detectable signal.

6. The method according to any one of claims 2 to 5, wherein the test substances are low molecular weight substances, peptides, aptamers, antibodies and / or fragments or derivatives thereof.

A process according to any one of claims 2 to 6, wherein the process is carried out in a host.

8. The method according to any one of claims 2 to 7, wherein the method is carried out as a high-throughput method.

9. The method according to any one of claims 2 to 8, wherein the method is performed computer assisted.

10. A method for improving the pharmacological properties of the identified by the method according to any one of claims 2 to 9

Test substances, wherein one

(A) the binding site of the test substance to the nucleic acid molecule or to the (poly) peptide and optionally the binding site of the nucleic acid molecule or of the (poly) peptide to the test substance identified;

(b) modifying the binding site of the test substance and the nucleic acid molecule or the (poly) peptide by molecular modeling; and

1 1. The method of claim 10, wherein the binding site in step (a) is determined by site-specific mutagenesis.

12. A method of modifying a test substance, which is identified or improved by the method according to any one of claims 2 to 1 1, wherein the test substance is further modified as a lead structure to (i) a modified active site, a modified spectrum of activity and / or a modified organ specificity and / or

(ii) an improved activity and / or

(iii) decreased toxicity (an improved therapeutic index) and / or

(iv) reduced side effects and / or

(vi) altered pharmacokinetic parameters (in particular resorption, distribution, metabolism and / or excretion) and / or

(vii) modified physicochemical parameters, especially solubility, hygroscopic properties, color, taste, odor, stability and / or shape, and / or

(viii) improved general specificity, organ / tissue specificity, and / or

(ix) an optimized administration form and / or route, in particular by

(a) esterification of carboxyl groups and / or

(b) esterification of hydroxyl groups with carboxylic acids and / or

(d) formation of pharmaceutically acceptable salts and / or

(e) formation of pharmaceutically acceptable complexes and / or

(f) synthesis of pharmacologically active polymers and / or

(g) introduction of hydrophilic groups and / or (h) introduction and / or replacement of substituents in aromatics and / or side chains and / or modification of the substituent pattern and / or (i) modification by introduction of isosteric and / or bioisosteric groups and / or

(j) synthesis of homologous compounds and / or (k) introduction of branched side chains and / or

(1) Conversion of alkyl substituents to cyclic analogues and / or (m) derivatization of hydroxyl groups to ketals and / or

Acetals and / or

(n) N-acetylation to amides and / or phenyl carbamates and / or

(o) synthesis of Mannich bases and / or imines and / or

(p) conversion of ketones and / or aldehydes in Schiff bases, oximes, acetals, ketals, enol esters, oxazolidines, thiozolidines or combinations thereof.

13. The method according to any one of claims 2 to 12, wherein the identified, improved and / or modified test substance is pharmacologically further improved by Peptidomimetika.

14. Use of an inhibitor and / or repressor of a depression-inducing and / or depression-associated nucleic acid molecule, in particular a gene and / or its DNA sequence and / or its associated RNA sequence, for the production of a medicament for the prophylactic and / or curative treatment of depression ,

15. Use of an inhibitor and / or repressor of a depression-inducing and / or depression-associated nucleic acid molecule, in particular gene and / or its DNA sequence and / or its associated RNA sequence, coded (poly) peptide for the manufacture of a medicament or medical device for the prophylactic and / or curative treatment of depression.

16. Use according to claim 14 or 15, wherein an identified according to the method of any one of claims 2 to 13 test substance is used as inhibitor and / or repressor.

17. Use of at least one substance for the production of a medicament or medicament for the prophylactic and / or curative treatment of depression, wherein the substance regulates, in particular reduces or at least inhibits, the gene activity and / or gene expression of at least one depression-inducing and / or depressurization-inducing gene ,

18. Use according to claim 17, wherein the substance interacts with the promoter and / or enhancer of the depression-inducing and / or associated gene and / or interacts in such a way that the binding of in particular endogenous transcription factors, in particular activators, to the promoter and / or Enhancer is prevented or at least inhibited.

19. Use according to claim 17, wherein the substance interacts with a particular endogenous transcription factor, in particular activator, in such a way that the binding of the transcription factor, in particular activator, to the promoter and / or enhancer of the depression-inducing and / or depression-inducing gene is prevented or at least inhibited ,

20. A method for determining the risk of a subject suffering from depression and / or for predicting individual drug effects, and / or side effects, in particular depression as a result of interferon therapy, whereby the subject is assigned an increased risk of disease and / or changed the subject Drug effects and / or side effects are assigned in the event that the subject increased gene activity and / or Genex- having at least one depression-inducing and / or depression-associated gene.

21. The method according to claim 20, wherein the drug is in particular in the context of the treatment and / or therapy of hepatitis, in particular chronic hepatitis type C, administered α-interferon, in particular pegylated α-interferon.

22. A method for the identification and / or determination of at least one depression-inducing and / or depression-associated nucleic acid molecule, in particular of a gene, preferably a depression-inducing and / or depression-associated gene associated with the administration of interferon or else one related to endogenous depression standing depression-inducing and / or depression-associated gene, the method comprising the following steps:

(a) Generation of a gene expression and / or gene activity profile from a multiplicity of probands of a subject collective who are each treated with interferon;

(b) Analysis and comparison or comparison of the respective gene expression and / or gene activity profiles of (i) subjects suffering from depression on the one hand and interferon therapy on the other hand or especially in the case of endogenous depression Analysis and comparison or comparison of the respective gene expression and / or gene activity profiles of (i) subjects suffering from endogenous depression on the one hand and (ii) subjects not suffering from endogenous depression on the other hand and

(c) Identification of at least one nucleic acid molecule, in particular of at least one gene which exhibits increased gene expression and / or gene activity in (i) the subjects suffering from depression in comparison to (ii) the subjects not suffering from depression.

23. The method of claim 22, wherein following step (c), the method comprises the following step:

(d) assignment of the nucleic acid molecule, in particular gene, identified in step (c) as a depression-inducing and / or depression-associated nucleic acid molecule, in particular depression-inducing and / or depression-associated gene, preferably as depression-inducing and / or depression-associated with the administration of interferon Gene or, in the case of endogenous depression, preferably as a depression-inducing and / or depression-associated gene associated with endogenous depression.

24. A method according to claim 22 or 23, wherein the administration of interferon is associated with the therapy of hepatitis, especially hepatitis type C.

25. Use according to any one of claims 1 or 14 to 19 or method according to any one of claims 2 to 13 or 20 to 24, wherein the gene is selected from the group of

MEF2A, in particular with the transcript ID (locus) NM 005587, in particular according to SEQUENCE LISTING SEQ. ID. NO. 2 and / or Table 1, - TORIB, in particular with the transcript ID (locus) NM O 14506, in particular according to SEQUENCE LISTING SEQ. ID. NO. 3 and / or Table 1,

DISCl, in particular with the transcript ID (locus) NM_018662, in particular according to SEQUENCE LISTING SEQ. ID. NO. 4 and / or Table 1, GCH1, in particular with the transcript ID (locus) NM 000161, in particular according to SEQUENCE LISTING SEQ. ID. NO. 5 and / or Table 1, - ST3GAL5, in particular with the transcript ID (locus)

NM 003896, in particular according to SEQUENCE LISTING SEQ. ID. NO. 6 and / or Table 1,

- PSMB9, in particular with the transcript ID (locus) NM 002800, in particular according to SEQUENCE LISTING SEQ. ID. NO. 7 and / or Table 1,

RBCK1, in particular with the transcript ID (locus) NM 006462, in particular according to SEQUENCE LISTING SEQ. ID. NO. 9 and / or Table 1, and

- ZNF200, in particular with the transcript ID (locus) NM 003454, in particular according to SEQUENCE LISTING SEQ. ID. NO. 10 and / or Table 1, - STATl, in particular with the transcript ID (locus) NM_007315, in particular according to SEQUENCE LISTING SEQ. ID. NO. 1 1 and / or Table 2,

RTP4, in particular with the transcript ID (locus) NM 022147, in particular according to SEQUENCE LISTING SEQ. ID. NO. 12 and / or Table 2,

- GBPl, in particular with the transcript ID (locus) NM_002053, in particular according to SEQUENCE LISTING SEQ. ID. NO. 14 and / or Table 2, CCL8, in particular with the transcript ID (locus) NM_005623, in particular according to SEQUENCE LISTING SEQ. ID. NO. 15 and / or Table 2, - TNFSF 10, in particular with the transcript ID (locus) NM 003810, in particular according to SEQUENCE LISTING SEQ. ID. NO. 16 and / or Table 2, as well as their combinations.

26. Use according to one of claims 1 or 14 to 19 or method according to one of claims 2 to 13 or 20 to 24, wherein the gene is selected from the group of - DYNLT 1, in particular with the transcript ID (locus) NM 006519 , in particular according to SEQUENCE LISTING SEQ. ID. NO. 1 and / or Table 1,

MEF2A, in particular with the transcript ID (locus) NM_005587, in particular according to SEQUENCE LISTING SEQ. ID. NO. 2 and / or Table 1,

DISCl, in particular with the transcript ID (locus) NM 0 18662, in particular according to SEQUENCE LISTING SEQ. ID. NO. 4 and / or Table 1,

GCH1, in particular with the transcript ID (locus) NMJ) OO 161, in particular according to SEQUENCE LISTING SEQ. ID. NO. 5 and / or Table 1, - ST3GAL5, in particular with the transcript ID (locus)

NM_003896, in particular according to SEQUENCE LISTING SEQ. ID. NO. 6 and / or Table 1,

- PSMB9, in particular with the transcript ID (locus) NM 002800, in particular according to SEQUENCE LISTING SEQ. ID. NO. 7 and / or Table 1, - GLRX, in particular with the transcript ID (locus) NM 002064, in particular according to SEQUENCE LISTING SEQ. ID. NO. 8 and / or Table 1, - RBCKl, in particular with the transcript ID (locus) NM_006462, in particular according to SEQUENCE LISTING SEQ. ID. NO. 9 and / or Table 1, and

- ZNF200, in particular with the transcript ID (locus) NM 003454, in particular according to SEQUENCE LISTING SEQ. ID. NO. 10 and / or Table 1, and combinations thereof, preferably from the group of DYNLTl, MEF2A, TORlB, DISCl,

GCHl and ST3GAL5, in particular as previously defined.

27. Use according to any one of claims 1 or 14 to 19 or method according to any one of claims 2 to 13 or 20 to 24, wherein the gene is selected from the group of

CCL8, in particular with the transcript ID (locus) NM 005623, in particular according to SEQUENCE LISTING SEQ. ID. NO. 15 and / or Table 2, TNFSF10, in particular with the transcript ID (locus) NM 003810, in particular according to SEQUENCE LISTING SEQ. ID. NO. 16 and / or Table 2, as well as their combinations.

28. Use according to any one of claims 1, 14 to 19 and 25 to 27 or method according to one of claims 2 to 13 and 20 to 27, wherein the depression in connection with the treatment and / or therapy of hepatitis, in particular chronic hepatitis type C , stands.

29. Use according to any one of claims 1, 14 to 19 and 25 to 27 or method according to any one of claims 2 to 13 and 20 to 27, wherein the depression is associated with α-interferon, in particular pegylated α-interferon, and / or is caused thereby, in particular wherein the depression is by a preferably systemic application of α-interferon, in particular pegylated α-interferon, in particular in the context of the treatment and / or therapy of hepatitis, in particular chronic hepatitis type C, is and / or thereby forth - is called.

30. Use according to any one of claims 1, 14 to 19 and 25 to 27 or method according to any one of claims 2 to 13 and 20 to 27, wherein the depression associated with increased gene activity and / or gene expression of at least one in any of claims 25 up to 27 defined gene and / or caused thereby, in particular wherein the gene activation by a preferably systemic application of α-interferon, in particular pegylated α-interferon, in particular in the context of the treatment and / or treatment of hepatitis, especially chronic hepatitis type C, is related and / or caused thereby.

31. Use according to any one of claims 1, 14 to 19 and 25 to 27 or method according to any one of claims 2 to 13 and 20 to 27, wherein the depression is an endogenous depression.