Methods and means of treating mental disorders

Abstract

The invention relates to a combination of testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for administration to subjects in need thereof for improvement of a cognitive disorder, sexual dysfunction, or mood disorder that can advantageously be applied with Repetitive Transcranial Magnetic Stimulation (rTMS) and / or cognitive training.

Description

Field of the invention The invention relates to a combination of testosterone and oxytocin for administration to individuals for improvement of a cognitive disorder, sexual dysfunction, ormood disorderthat can be applied with Repetitive Transcranial Magnetic Stimulation (rTMS) and / or cognitive training, preferably comprising administering one of the active ingredients, rTMS and / or cognitive training prior to the other of the active ingredients, rTMS and / or cognitive training, optionally wherein the one ofthe active ingredients, rTMS and / or cognitive training is further administered with the other of the active ingredients, rTMS and / or cognitive training. Background of the invention Mental disorders are characterized by a clinically significant disturbance in an individuals cognition, emotional regulation, or behavior, often in a social context. They are usually associated with distress or impairment in important areas of functioning. There are many different types of mental disorders, some examples of which are cognitive disorders (such as mild cognitive impairment (MCI) and dementia), sexual dysfunctions (such as sexual interest / arousal disorder and / or erectile dysfunction), and mood disorders (such as depression and social anxiety). Treatment of mental disorders typically depends on the type, its severity, and response of an individual patient to specific treatments. Examples of treatment modalities include drugs, brain- stimulation, and psychotherapy. However, due to the high complexity of the human brain, its individual development during the lifespan ofthe human, other individual biological differences, and the social and lifestyle circumstances in which a person lives, responses to treatment of mental disorders generally results in a high interindividualvariability. Hence, there remains a need for more effective and reliable treatment of mental disorders, in particularwhen assessed in view of a group of patients suffering from a specific mental disorder. The current inventors now provide for means and methods that are useful for the treatment of subjects suffering from a cognitive disorder, sexual dysfunction, or mood disorder. Summary of the invention The current inventors provide a combination treatment ofa subject suffering from a cognitive disorder, sexual dysfunction, ormood disorder (like depression and / or social anxiety) involving on one hand the administration of compounds, namely testosterone and oxytocin, and on the other hand applying repetitive transcranial magnetic stimulation (rTMS) pulses to the brain of the subject and / or exposing the subject to cognitive training, which results in a more effective treatment ofthe disorder. Preferably, testosterone is administered sublingually and oxytocin intranasally. Preferably, testosterone and oxytocin are administered in a specific sequence in time. This improved effect can be more pronounced when one of the treatment modalities is at least applied prior to the other treatment modalities and then preferably continued together with the other treatment modalities. For example, applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training at least before administering testosterone and oxytocin results in a more effective treatment. On the other hand, administering testosterone and oxytocin at least prior to applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training also results in a more effective treatment. lmportantly, as discussed in more detail herein, the different treatments reinforce each other towards the desired effect and are preferably applied in a certain period of time. Thus, herein is provided testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from a cognitive disorder, sexual dysfunction, or mood disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and c. i. applying repetitive transcranial magnetic stimulation (rTMS) pulses to the brain of the subject; and / or ii. exposing the subject to cognitive training; thereby treating the subject suffering from the cognitive disorder, sexual dysfunction, or mood disorder. Suitably, one of a to c may be performed at least before the other two of a to c. Suitably, the one of a to c may be subsequently performed together with the other two of a to c, and / or following the other two of a to c. Suitably, the treatment may comprise concurrent treatment of a to c. Suitably, two of a to c may be performed at least before the other one of a to c. Suitably, the two of a to c may be subsequently performed together with the other one of a to c, and / or following the other one of a to c. Herein, in the context ofa to c, it is understood that this indicates a, b, and c, and a indicates administering an effective dosage of testosterone and / or a functional analogue thereof, b indicates administering an effective dosage of oxytocin and / or a functional analogue thereof, and c indicates i. applying repetitive transcranial magnetic stimulation (rTMS) pulses to the brain ofthe subject; and / or ii. exposing the subject to cognitive training. Herein is also provided a method of treatment of a subject suffering from a cognitive disorder, sexual dysfunction, or mood disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and c. i. applying rTMS pulses to the brain of the subject; and / or ii.exposing the subject to cognitive training. Also is provided herein testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from a cognitive disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and c. i. applying rTMS pulses to the brain of the subject; and / or ii.exposing the subject to cognitive training; wherein one ofa to c, preferably c, is performed at least before the othertwo ofa to c, thereby treating the subject suffering from the cognitive disorder. Herein is also provided testosterone and / or a functional analogue thereofand oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from a sexual dysfunction, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and c. i. applying rTMS pulses to the brain of the subject; and / or ii.exposing the subject to cognitive training, preferably exposing the subject to cognitive training; thereby treating the subject suffering from the sexual dysfunction. Also is provided herein testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from a mood disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; and b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and optionally c. i. applying rTMS pulses to the brain of the subject; and / or ii.exposing the subject to cognitive training; thereby treating the subject suffering from the mood disorder. Provided herein is also testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from a cognitive disorder, sexual dysfunction, or mood disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; and b. administering an effective dosage of oxytocin and / or a functional analogue thereof; wherein the subject has been treated before the administering of the effective dosage of testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof such that cognitive function of the subject is improved . Also provided herein is a method of selecting a subject suffering from a cognitive disorder, sexual dysfunction, ormood disorder having increased benefit ofa treatment comprising administering testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof, the method comprising: a. determining cognitive function of the subject and / or an improvement of cognitive function of the subject compared to a previous point in time; b. selecting the subject for the treatment comprising administering testosterone and / or a functional analogue thereofand oxytocin and / ora functional analogue thereof ifthe subject has cognitive function in the top 80% of a general reference population, the top 70% of a general reference population, the top 60% of a general reference population, the top 50% of a general reference population, the top 40% ofa general reference population, the top 30% ofa general reference population, orthe top20% ofa general reference population, and / or a signicant improvement of cognitive function compared to a previous point in time. Also provided herein is a method of selecting a subject suffering from a cognitive disorder, sexual dysfunction, ormood disorder having increased benefit ofa treatment comprising administering testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof, the method comprising: a. determining cognitive function of the subject and / or an improvement of cognitive function of the subject compared to a previous point in time; b. selecting the subject for the treatment comprising administering testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof if: i. the subject has cognitive function in the lowest 50% of a general reference population, the lowest 40% of a general reference population, the lowest 30% of a general reference population, or the lowest 20% of a general reference population, and / or a signicant improvement of cognitive function compared to a previous point in time; and / or. ii. the subject suffers cognitive dysfunction according to diagnostic criteria according to formal classification systems, such as the various versions ofthe Diagnostic and Statistical Manual of Mental Disorders (DSM), preferably version DSM-5 or DSM-5-TR (Le, a set of signs, symptoms, and tests used to determine a person's diagnosis). Definitions As used herein, the terms treat, treating and "treatment" are taken to include an intervention performed with the intention of preventing the development or altering the pathology of a condition, disorder orsymptom. Accordingly, "treatment" refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted condition, disorder or symptom. As used herein, the term free testosterone refers to a short, sharp peak level of free testosterone of at least 0.020 nmol / l in the blood circulation of a (human) subject. Testosterone in the blood circulation is mostly bound by steroid hormone binding globulin (SHBG) or by albumin. The peak plasma level of testosterone should be present and calculated as free testosterone, and therefore be a fraction not bound by albumin or SHBG. Testosterone should be provided in a high enough dose to saturate the albumin and SHBG in the circulation. ln other words, the concentration of testosterone and / or a functional analogue thereof has to be at a level to overcome direct and complete binding of testosterone by SHBG or albumin. Alternatively, the skilled person may use other suitable means or methods of avoiding or reducing binding of testosterone and / or a functional analogue therefore to albumin orSHBG. A non-limiting example may be using a competitor of the testosterone binding site on SHBG. As used herein, the term cyclodextrin, includes displacement enhancers such as poly- betacyclodextrin, hydroxypropylbeta-cyclodextrin, and gamma cyclodextrin. As used herein, the term sublingual formulation, refers to a formulation ofan active ingredient that is suitable for administration under the tongue. Such a sublingual formulation allows the release of an active ingredient when held in the oral cavity, e.g. beneath the tongue, and allows the active ingredient to diffuse into the blood. Release of the active ingredient is preferably achieved within minutes. A sublingual formulation may also be termed a hypoglossal or subglossal formulation. A preferred example of an active ingredient is testosterone and / or a functional analogue thereof. As used herein, the term sublingual, also refers to the space between the lips and the teeth and the space between the cheek and the teeth, also known as the buccal space. The sublingual area may include the area between the palate and tongue and further includes the true sublingual area. As used herein, the term sexual dysfunction refers to a subject that experiences troubles during any stage of normal sexual activity, which may include physical pleasure, preference, arousal, desire, or orgasm. Sexual dysfunction can therefore have a profound impact on an individual's perceived quality of sexual life. Sexual dysfunction may suitably be defined as a "person's inability to participate in a sexual relationship as they would wish". Such an individual typically feels extreme distress and interpersonal strain for at least six months. Detailed description of the invention It is an object ofthe invention to provide testosterone and / ora functional analogue thereofand oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from a cognitive disorder, sexual dysfunction, or mood disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and c. i. applying repetitive transcranial magnetic stimulation (rTMS) pulses to the brain of the subject; and / or ii. exposing the subject to cognitive training; thereby treating the subject suffering from the cognitive disorder, sexual dysfunction, or mood disorder. Suitably, one of a to c may be performed at least before the other two of a to c. Suitably, the one of a to c may be subsequently performed together with the other two of a to c, and / or following the other two of a to c. Suitably, the treatment may comprise concurrent treatment of a to c. Suitably, two of a to c may be performed at least before the other one of a to c. Suitably, the two of a to c may be subsequently performed together with the other one of a to c, and / or following the other one of a to c. Another object of the invention is to provide testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from a cognitive disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and c. i. applying rTMS pulses to the brain of the subject; and / or ii.exposing the subject to cognitive training; wherein one ofa to c, preferably c, is performed at least before the othertwo ofa to c, thereby treating the subject suffering from the cognitive disorder. Another object of the invention is to provide testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from a sexual dysfunction, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and c. i. applying rTMS pulses to the brain of the subject; and / or ii.exposing the subject to cognitive training; thereby treating the subject suffering from the sexual dysfunction. Another object of the invention is to provide testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from a mood disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; and b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and optionally c. i. applying rTMS pulses to the brain of the subject; and / or ii.exposing the subject to cognitive training; thereby treating the subject suffering from the mood disorder. Another object of the invention is to provide testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from an anxiety disorder, preferably a social anxiety disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; and b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and optionally c. i. applying rTMS pulses to the brain of the subject; and / or ii.exposing the subject to cognitive training; thereby treating the subject suffering from the anxiety disorder, preferably the social anxiety disorder. Another object of the invention is to provide testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from a depressive disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; and b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and optionally c. i. applying rTMS pulses to the brain of the subject; and / or ii.exposing the subject to cognitive training; thereby treating the subject suffering from the depressive disorder. V\thout being bound by theory, in the present invention because of the different underlying mechanisms of action of (sublingual) testosterone and / or oxytocin, which may include functional analogues thereof, areas in the brain that are affected by one ofthe disorders from the group cognitive disorders, sexual dysfunctions, and mood disorders (for example depression and / or social anxiety), are affected on a biological level (e.g. via neurogenesis and / or brain plasticity) and improved with regard to the relevant clinically significant disturbances associated with the respective disorder. Again, without being bound by theory, applying rTMS pulses to the brain of the subject can result in positive effects on cognitive functions and significant growth in gray matter volume and improvement of white matter integrity in certain brain areas, while cognitive training can result in structural improvements in gray matterchanges in neuronal networks in the brain involved in cognitive function and can have beneficial effects on improving white matter microstructure in frontal and medial brain regions. Hence, applying rTMS pulses and cognitive training result in an improvement of cognitive functions. The combination of the above treatment modalities results in a more effective treatment of a subject suffering from a cognitive disorder, sexual dysfunction, or mood disorder (for example depression and / or social anxiety). The different interventions not only contribute but also greatly increase the intended effect. This approach largely abolishes the variance of effects seen in a single treatment approach. Individual effects and effect sizes become larger, and interindividual differences in the effects become increasingly smaller. In addition, applying one ortwo ofthe treatment modalities at least before applying the other treatment modalities leads to an even greater treatment effect. Without being bound by theory, it is thought that such an initial treatment affects the subject on an individual and biological level making it more susceptible to subsequent treatment by the following combination treatment, thereby reducing interindividual effects on a patient group level. For example, executive cognitive functions, including working memory, behavioural and cognitive inhibition and flexibility, can be highly improved because of the different underlying mechanisms of action of testosterone and / or oxytocin. Such a combinatorial treatment (for e.g. a subject suffering from a cognitive disorder) provides for a strong improvement of cognitive functions, which is further improved by combining with cognitive training and / or applying rTMS pulses to the brain ofthe subject. An even furtherimprovement is achieved by at least applying one ortwo ofthe treatment modalities (i.e. testosterone, oxytocin, rTMS pulses, and cognitive training) priorto the othertreatment modalities and preferably subsequently continuing (concurrent) combinatorial treatment of all the modalities. Concurrent administration of testosterone and oxytocin and at least one of cognitive training and applying rTMS pulses to the brain of the subject also results in improved treatment effectiveness. In another example, testosterone and oxytocin have the potential to reinforce each other, i.e. testosterone increases sexual motivation and oxytocin enhances the feeling of partner bonding. Without being bound by theory, highly advantageously, the different mechanisms of actions combined can bridge the distinction in two previously distinguished subgroups in sexual dysfunctions (low sensitivity to sexual stimuli / cues vs. high activity of sexual inhibitory mechanisms). This combinatorial treatment (for e.g. a subject suffering from a sexual dysfunction) is further improved by combining with cognitive training and / or applying rTMS pulses to the brain ofthe subject. An even furtherimprovement is achieved by at least applying one or two of the treatment modalities (i.e. testosterone, oxytocin, rTMS pulses, and cognitive training) prior to the other treatment modalities and preferably subsequently continuing (concurrent) combinatorial treatment of all the modalities. Concurrent administration of testosterone and oxytocin and at least one of cognitive training and applying rTMS pulses to the brain ofthe subject also results in improved treatment effectiveness. Furthermore, again without being bound by theory, oxytocin provides social bonding for the in-group (relative to the patient), butmay have the opposite effect on the out-group (relative to the patient).A patients partner who is the object of the patients sexual dysfunction can quickly become part of the out-group. Thus, oxytocin alone may actually worsen symptoms. This can be treated with applying rTMS pulses to the brain of the subject and / or cognitive training. For example by training (conditioning) the subject with a cognitive task to automatically focus their attention, which is a cognitive function, on positive stimuli (e.g. happy faces), which furthermay include a training task to get a positive interpretation. ln another example, testosterone and oxytocin have the potential to reinforce each other, i.e., testosterone reduces depressed mood and oxytocin enhances social bonding. Such a combinatorial treatment provides for a strong improvement of mood disorders, which is further enhanced by combining it with cognitive training and / or by applying rTMS pulses to the subjects brain. Even further enhancement is achieved by applying at least one of the treatment modalities (i.e., testosterone, oxytocin, rTMS pulses, and cognitive training) prior to the other treatment modalities and preferably subsequently continuing combinatorial treatment of all the modalities. Concurrent administration of testosterone and oxytocin and at least one of cognitive training and applying rTMS pulses to the brain ofthe subject also results in improved treatment effectiveness. As discussed in more detail below, regarding concurrent administration of testosterone and oxytocin and / or functional analogues thereof as set out above, is preferably not administered at the same time. Administration, preferably sublingual, oftestosterone and / or a functional analogue thereof, is preferably performed first, and, subsequently, secondly, oxytocin and / or a functional analogue thereof is administered, preferably intranasally, in such a dosing regimen such that the sensitivity windows for testosterone (e.g. from about 2.56 hours after sublingual administration) and oxytocin (e.g. from about 15 minutes to 90 minutes after intranasal administration) overlap. Testosterone is known to increase the brain's sensitivity to cues associated with behavior driven by social interaction. Testosterone (17-[3-hydroxyandrost-4-en-3-one) is commercially available and can be obtained by various ways. As used herein, the term functional analogue of testosterone refers to any useful metabolite or precursor of testosterone. An example is dihydrotestosterone, which may provide the same function as testosterone. Dosage, duration and / or time of administration of a functional analogue of testosterone may be suitably adjusted by the skilled person relative to a selected dosage, duration and / or time point of administration of testosterone. Oxytocin is a nonapeptide and a mammalian hormone. Oxytocin is typically administered as a liquid formulation via injection or as a nasal spray. Oxytocin and functional analogues thereof are commercially available, for example as ready-to-use liquid formulations. Functional analogues of oxytocin are known, forexample carbetocin and desamino-oxytocin.A functional analogue of oxytocin may include any useful derivative or precursor of oxytocin that can provide for essentially the same function as oxytocin. Preferably, the route of administration of testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof in non-invasive. Cognitive functions and other mental functions may be negatively affected by repeated stressful events. Treatment according to the invention can include multiple administrations, which may therefore incur multiple stressful events to the subject, which may subsequently adversely affect motivation for cognitive training. Non-invasive treatment is therefore preferred. Preferably, the subject according to the disclosure is a human subject. Suitably, testosterone and / or a functional analogue thereof for use according to the invention may be provided by a route of administration, for example via oral, buccal or intranasal administration, or via inhalation, for example via a nebulizer. Preferably, testosterone and / or a functional analogue thereof may be administered via oral administration. Suitably, oral administration may comprise administering a liquid formulation or a sublingual formulation. Suitably, the sublingual formulation may comprise a displacement enhancer, for example, a cyclodextrin. Oral administration of testosterone is a comfortable option with minimal side effects. Oral administration of testosterone may increase adherence to treatment. Suitably, testosterone and / or a functional analogue thereof for use according to the invention may be administered in the form of a sublingual formulation, preferably wherein the formulation comprises cyclodextrin. Preferably, the testosterone and / or a functional analogue thereof may be provided such that a short, sharp peak level of testosterone is present about 10-30 minutes after administration of the testosterone and / or a functional analogue thereof. Preferably, the short, sharp peak level of testosterone may be provided as a short, sharp peak level of free testosterone in the blood circulation of the human. Methods for determining the amount of free testosterone are known in the art. For example in Lavoie et al., 1989. Clinical Biochemistry 22: 451-456. Without being bound by theory, administration oftestosterone according to the invention above a certain threshold value results in a pharmacological peak in testosterone. Above that threshold, administration of testosterone is accompanied by an increase in free testosterone. Free testosterone can have a biological effect. An increase in testosterone does not have an immediate effect on certain stimulus-response relationships. An increase in free testosterone in the circulation is associated approximately 3 to 6 hours later with a greater sensitivity of brain areas to certain stimuli-response effects (i.e. stimuli that are sensitive to testosterone, which may include, but not be limited to, all kinds of cognitive functions). Testosterone administered e.g. sublingually with cyclodextrins (for women about 0.1 to 2 mg; for men about 0.5 to 20 mg) causes a pharmacological peak in testosterone after about 15 minutes. Such a pharmacological peak can cause, for example in a period of 3 to 6 hours after administration, a greater sensitivity ofthe brain to stimuli and therefore forexample, an increasing effect on cognitive function. Suitably, the total amount of testosterone and / or a functional analogue thereof, such as dihydrotestosterone, that is provided to a subject in need thereofmay be between 0.1 and 20 milligram. When the subject is a male, the testosterone and / or a functional analogue thereof, such as dihydrotestosterone, is preferably administered in a total amount of between 0.5 and 20 milligram, preferably between 1 and 10 milligram, including between 5 and 10 milligram. When the subject is a female, the testosterone and / or a functional analogue thereof, such as dihydrotestosterone, is preferably administered in a total amount of between 0.1 and 2 milligram, preferably between 0.25 and 1 milligram, such as between 0.3 and 0.7 milligram, including about 0.4 milligram, about 0.5 milligram and 0.6 milligram. Suitably, testosterone and / or a functional analogue thereofmay comprise testosterone and / or dihydrotestosterone. Suitably, a mixture comprising testosterone and dihydrotestosterone may comprise the testosterone and dihydrotestosterone in a ratio of between 10:90 and 90:10 (weight / weight). Suitably, a ratio of between 20:80 and 80:20 (weight / weight), preferably between 30:70 and 70:30 (weight / weight), such as between 40:60 and 60:40 (weight / weight), including about 50:50 (weight / weight). Suitable, the ratio may be about 25:75, about 30:70, about 40:60, or about 45:55 (w / w). Preferably, administration of testosterone and / or a functional analogue thereof, such as dihydrotestosterone, is via oral administration, preferably by sublingual administration. Preferably, the sublingual formulation is provided as an immediate release delivery system for oral administration that is formulated to provide a peak level of free testosterone of at least 0.020 nmol / l in the blood circulation. Suitably, testosterone and / or a functional analogue thereof for use according to the invention is formulated to provide upon administration a peak level of free testosterone of 0.020 nmol / L or more for females and 0.4 nmol / L or more for males in the blood circulation of the subject. Suitably, testosterone and / or a functional analogue thereof is formulated to provide upon administration a peak level of free testosterone of 0.020 nmol / L for females and 0.4 nmol / L for males in the blood circulation ofthe subject. Preferably, an immediate release delivery system for oral administration according to the invention comprises a core and a coating surrounding the core, wherein the coating comprises the testosterone and / or a functional analogue thereof, such as dihydrotestosterone, and further comprising a cyclodextrin. Suitably, the coating may further comprise a cellulose such as agglomerated cellulose, microcrystalline cellulose, or a combination thereof. Suitably, the cellulose is selected from methylcellulose, hydroxypropyl methylcellulose, and carboxy methyl cellulose. Preferably, the cellulose is or comprises hydroxypropyl methylcellulose. A carrier such as a cyclodextrin combined with testosterone and / or a functional analogue thereof provides for rapid and efficient delivery ofthe testosterone and / ora functional analogue thereof, such as dihydrotestosterone, to the mucous membrane, from which the testosterone and / or a functional analogue thereof is then rapidly absorbed into the circulation. Oxytocin acts as a neurotransmitter and hormone . Oxytocin is also released in the brain, where it modulates various aspects of social behavior. For example, oxytocin enhances social reward, promotes maternal nurturing and attachment, and increases salience ofcertain social stimuli. Oxytocin improves bonding behavior and social memory in monogamous species. Physiological properties of oxytocin in the brain are associated with fluctuations in the amount of oxytocin present during different occurrences and different projections of oxytocin in the brain. In addition, oxytocin interacts with other systems such as the dopaminergic and serotonergic systems. Hence, oxytocin lacks clear spatial and temporal specicity, but has widespread effects on intrinsic brain functioning. Studies using functional magnetic resonance imaging (fMRl) with oxytocin administration reveal a specific set of social brain regions through which oxytocin influences human behavior. Oxytocin has the potential to modulate activity in specific brain regions. In addition, oxytocin has the potential to modulate the functional connectivity between these regions involved in social behavior (e.g. pair bonding, sexual behavior, social bonding). Moreover, oxytocin is involved in neurogenesis and neuroplasticity ofthe brain, improving cognitive (executive) functions such as short- and long-term memory. lntranasal administration of oxytocin causes an increase in oxytocin levels in the blood circulation within a few minutes, with the T-max occurring after approximately 15 minutes and returns to baseline after approximately 90 minutes. Means and methods to determine oxytocin levels in the blood are known in the art. The majority of studies that have investigated oxytocin having effect on behaviorand the like use dosages between 20 to 50 IE ofoxytocin, typically 24 IE. Behavioral and neural effects of administered dosages are around 15 to 90 minutes after administration. As discussed above, the effect on the brain's sensitivity to cues associated with behavior by testosterone and / or functional analogue thereof has a delay, after (sublingual) administration, ofabout 2.5 to 6 hours, which may be around 3 to 4.5 hours, in particular around 4 hours. Furthermore, there is a delay for the effect on the brain's sensitivity to cues associated with behavior by oxytocin and / or a functional analogue thereof, which is around 15 to 90 minutes after (intranasal) administration. Hence, testosterone and oxytocin, and / or functional analogues thereof, preferably are not administered at the same time. Preferably, sublingual administration of testosterone and / or a functional analogue thereof is performed first, and, subsequently oxytocin is administered, intranasally, in such a closing regimen such that the sensitivity windows for testosterone (e.g. from about 2.5 to 6 hours after sublingual administration) and oxytocin (e.g. from about 15 minutes to 90 minutes after intranasal administration) overlap. Suitably, administration of sublingual testosterone and / or a functional analogue thereof may be followed by administering of intranasal oxytocin and / ora functional analogue thereofduring a time window of about 3 to 6 hours after the peak concentration of testosterone in the blood circulation. lntranasal oxytocin may be preferably administered about 3.5 hours after the peak of testosterone. Thusly, the increased value of oxytocin associated with cognitive or other effects coincides with the period of highest behavioral effect of testosterone. Suitably, in one embodiment according to the invention, applying rTMS pulses to the brain may be performed 15 to 90 minutes after administration or intranasal administration of oxytocin. Suitably, for any which way of administration selected for both testosterone and oxytocin, the administration of testosterone and / or a functional analogue thereof may be to first provide a peak concentration of testosterone in the blood circulation, and second, the administration of oxytocin and / or a functional analogue thereof, is to provide a peak concentration of oxytocin and / or a functional analogue thereof, the peak concentrations separated from each other by about 3 to 4 hours. Suitably, applying rTMS pulses to the brain may be initiated, immediately, or shortly (for example less than 15 minutes, less than 14, less than 13, less than 12, less than 11, less than 10 minutes, orless) afterthe peak concentration of oxytocin and / or a functional analogue thereof is achieved. Preferably, this is selected to be within 15 to 90 min after intranasal oxytocin administration. A preferred route of administration of oxytocin is as a nasal spray, e.g. with a dose of4 IE per spray. The skilled person may appropriately use other suitable forms ofoxytocin and / orfurther suitable means according to the invention that can provide for an effect as observed with intranasally administered oxytocin and that may be suitable for the highly advantageous uses and methods in accordance with the invention, i.e. provide for likewise behavioral and neural effects as observed with intranasal administration. An example may be intravenous administration. Other examples may include, but not be limited to, administration of oxytocin in sublingual form, a limited sustained release form, intramuscular injection, via inhalation or a hydrogel. Suitably, testosterone and / or a functional analogue thereofand oxytocin and / ora functional analogue thereofmay be provided for use according to the invention wherein the effective dosage of oxytocin and / or a functional analogue thereof is administered in a form providing increased oxytocin levels 3 to 6 hours after administration of the testosterone and / or the functional analogue. Suitably, testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereofmay be provided for use according to the invention wherein the effective dosage of oxytocin and / or a functional analogue thereof is administered intranasally, which is preferably administered 3 to 4 hours after administration of the testosterone and / or the functional analogue. Preferably, the administration of oxytocin and / or a functional analogue thereof is about 3 hours and 30 minutes after administration of the testosterone and / or the functional analogue thereof, preferably wherein the testosterone and / or functional analogue is administered sublingually. Suitably, testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use according to the invention may be provided, wherein the effective dosage of oxytocin and / or a functional analogue thereof may be administered in a total amount in the range of 10 to 100 IE, preferably in the range of 20 to 50 IE. Such amounts preferably relate to intranasally administered amounts of oxytocin and / or a functional analogue, and alternative administration routes may involve equivalent amounts. Suitably, testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in a treatment according to the invention may be provided, wherein the treatment may further comprise applying repetitive transcranial magnetic stimulation (rTMS) pulses to the brain of the subject, having a stimuli frequency, number of pulses, and intensity sufficient to induce an electric field in the brain of the subject or increased neural activity in the brain of the subject, wherein the rTMS pulses are applied within a period of from 3 to 6 hours after the administration of testosterone and / or functional analogue thereof, wherein preferably, the administration of oxytocin and / or functional analogue thereof is administered about 210 minutes after the administration testosterone and / or the functional analogue thereof. Suitably, the rTMS pulses may be applied within a period of from 225 minutes and 315 minutes, preferably within a period of from 4 to 5 hours after the administration of testosterone and / or functional analogue thereof, wherein preferably, the administration of oxytocin and / or functional analogue thereof is administered about 210 minutes after the administration testosterone and / or the functional analogue thereof. Preferably, sublingual testosterone is administered, and subsequently intranasal oxytocin is administered about 210 minutes thereafter, wherein subsequently rTMS pulses are applied to the brain of the subject in a period of from about 225 minutes to 315 minutes after initial sublingual administration, the latter more preferably carried out in a period of from 4 hours to 5 hours. Various means and methods can be used to advantageously apply pulses of rTMS, including targeting different brain regions, different frequencies, different numbers and different intensities. Suitably, testosterone and / or a functional analogue thereof and oxytocin and / or functional analogue for use according to the invention may be provided, wherein the rTMS pulses are applied to the brain of the subject left, right or bilaterally applied to the prefrontal cortex. Suitably, the rTMS pulses may be applied left, right or bilaterally applied to the prefrontal cortex, including the dorsolateral prefrontal cortex (DLPFC) and / or inferior frontal gyrus (IFG). Suitably, the rTMS pulses may be applied left, right or bilaterally applied to the dorsolateral prefrontal cortex (DLPFC) and / or inferior frontal gyrus (IFG). Suitably, the rTMS pulses may be selected to have a stimuli frequency of 1 to 100 HZ. Suitably, the rTMS pulses applied may include high-frequent rTMS (hz>5) over the left DLPFC and / or low- frequent rTMS (hz<1) at the right DLPFC, and / or high frequent rTMS targeting the right IFG. Suitably, the rTMS pulses applied may include high-frequent rTMS (hz>5) over bilateral DLPFC. Suitably, the number ofrTMS pulses may be selected from the range of 100 to 3000. Suitably, the stimulus intensity of the applied rTMS may be selected from the range between 0.05 and 5 Tesla. Patients suffering from the disorders as described herein may benefitfrom multiple treatments. Suitably, testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof may be provided for use according to the invention, comprising administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof, as described herein, and subsequently applying rTMS pulses to the brain of the subject, as described herein, which are performed 1 to 7 times a week during a period 1 to 10 weeks, preferably 2 to 3 times a week for 5 weeks or more. According to the present invention, preferably after applying rTMS pulses to the brain of the subject, subjects may be subjected to cognitive training. Suitably, after applying rTMS may comprise subsequently thereafter, preferably immediately thereafter. However, it is understood that subjects may also be subjected to cognitive training without prior, concurrent, and / or subsequent rTMS treatment. Suitably, testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof may be provided for use according to the invention, comprising administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof, as described herein, applying rTMS pulses to the brain of the subject, and subsequently further comprises, exposing the subject to cognitive training. Suitably, the exposure to cognitive training may be an immediate subsequent exposure. Suitable cognitive training according to the invention may include training cognitive and / or executive functions, such as by learning or practicing chess, learning or practicing a musical instrument and / or singing with others (e.g. singing in a choir), all of the aforementioned preferably in a social setting. Accordingly, the treatments highly advantageously allow improving cognitive function. Improving cognitive function in accordance with the invention may include improving working memory. Various tests can be used to measure improvements in working memory. For example, the n-back test may be applied to test and confirm improvements in working memory. The n-back task is a continuous performance task that is commonly used as an assessment in psychology and cognitive neuroscience to measure a part of working memory and working memory capacity. The subject is presented with a sequence of stimuli, and the task consists of indicating when the current stimulus matches the one from n steps earlier in the sequence. The load factor n can be adjusted to make the task more or less difficult. Treatment in accordance with the invention, suitably the cognitive training in accordance with the invention, may comprise improving cognitive function, improving working memory, improving inhibition function, improving cognitive flexibility and / or halting or delaying progression of memory impairment. Such treatment and training may be highly useful for the treatment of a subject suffering from a cognitive disorder. Hence, treatment of a subject suffering from a cognitive disorder in accordance with the invention, suitably the cognitive training comprised therein, may comprise improving cognitive function, improving working memory, improving inhibition function, improving cognitive flexibility and / or halting or delaying progression of memory impairment. Cognitive training in accordance with the invention may comprise training cognitive and / or executive functions, non-limiting examples of which are learning or practicing chess (e.g. in a social setting), learning or practicing a musical instrument and / or singing with others (e.g. singing in a choir). In addition, the treatment in accordance with the invention may also be highly useful for the treatment of a subject suffering from a cognitive disorder, wherein the treatment comprises halting or delaying progression of memory impairment. Cognitive training comprised in a treatment of a subject suffering from a sexual dysfunction in accordance with the invention may comprise: automatically or subconsciously focusing attention of the subject towards one or more positive stimuli, wherein the one or more positive stimuli are interpreted more positively than before commencement of the cognitive training, preferably wherein the one or more positive stimuli comprise an image of a partner of the subject. Suitably, the cognitive training may further comprise learning not to automatically or subconsciously focus attention towards one or more negative stimuli. Cognitive training comprised in a treatment of a subject suffering from a mood disorder in accordance with the invention may comprise: automatically or subconsciously focusing attention of the subject towards one or more positive stimuli, wherein the one or more positive stimuli are interpreted more positively than before commencement ofthe cognitive training. Suitably, the cognitive training may further comprise learning not to automatically or subconsciously focus attention towards one or more negative stimuli. The use of testosterone and oxytocin combined with rTMS and / or cognitive training was found to be highly useful in the treatment of cognitive disorders. In a further embodiment, in accordance with the invention, a subject suffering from a cognitive disorder is selected from the group consisting of mild cognitive impairment (MCI) and dementia. In an embodiment the subject suffers from mild cognitive impairment (MCI), also known as mild neurocognitive disorder. In another embodiment the subject suffers from dementia, also known as major neurocognitive disorder. MCI can be thought of as a middle ground between normal aging and major neurocognitive disorder. Unlike delirium, mild neurocognitive disorders tend to develop slowly and are characterized by a progressive memory loss which may or may not progress to major neurocognitive disorder. In addition to memory loss and cognitive impairment, othersymptoms include aphasia, apraxia, agnosia, loss of abstract thought, behavioral / personality changes, and impaired judgment. Mild and major neurocognitive disorders are differentiated based on the severity of their symptoms. Also known as dementia, major neurocognitive disorder is characterized by significant cognitive decline and interference with independence, while mild neurocognitive disorder is characterized by moderate cognitive decline and does not interfere with independence. There are multiple testing methods known in the art to assess a subject's cognition and level of consciousness, including the Mini Mental Status Exam (MMSE), Montreal Cognitive Assessment (MoCA), Mini-Cog, and Cognitive Assessment Method (CAM), Glasgow Coma Score (GCS), Richmond Agitation and Sedation Scale (RASS), etc. The use of testosterone and oxytocin combined with rTMS and / or cognitive training was found to be highly useful in the treatment of sexual dysfunction. Sexual dysfunction causes symptoms such as a delayed, or loss of, sexual desire and / or arousal. Sexual arousal causes different physical changes, particularly in the sex organs. In sexually functional women, sublingual testosterone caused an increase in brain sensitivity to sexual cues after about three to four hours, which in turn affected physiological sexual response in preparation for sexual behaviour (Tuiten et al., 2000. Arch Gen Psychiatry 57: 149-53; Tuiten et al., 2002. Arch Gen Psychiatry 59: 465). Sexual arousal in men may suitably be determined by determining an increase in size of penis and testes due to blood flow during an initial phase, and presence or absence of an orgasm and / or ejaculation in a next phase. The determination of presence of an orgasm and / or ejaculation may include determining the intensity of the orgasm and / or ejaculation. Sexual arousal in women may suitably be determined by determining vaginal lubrication in anticipation of sexual intercourse. Further indicators of sexual arousal in females are erection of nipples, vasocongestion of the vaginal walls, tumescence and erection of the clitoris and labia, elevation ofthe cervix and uterus, and expansion ofthe back of the vagina, a change in shape, color and size of the labia majora and labia minora, and / or pupil dilation. Sexual desire, or libido, is a subjective awareness of desire for sexual satisfaction, irrespective of sexual activity. Sexual desire may suitably be determined by evaluation of an individual before and after administration in accordance with the invention of testosterone and / or a functional analogue and oxytocin and / or a functional analogue thereof. The evaluation preferably relates to the levels of desire before and after the treatment, to the number of sexually satisfying events, and to the individuals impression of improvement. A preferred evaluation is provided by questionnaire and / or Sexual Event Diary (SED). SED is preferably completed at home within 24 hours of each sexual event. The SED measures different aspects ofsexual satisfaction ofa single sexual event using Likert-type scale items and binary questions. Examples of sexual events are sexual desire, mental arousal, physical arousal, sexual pleasure, level of distraction, level of ability to let go, orgasm, and satisfaction. SED scores are preferably summarized per individual per regime, but only for those sexual events during which medication was used. Suitably, the subject suffering from sexual dysfunction may be selected from the group consisting of (Female) Sexual Interest / Arousal Disorder (FSIAD), (Female) Orgasmic Disorder, Hypoactive Sexual Desire Disorder (HSDD), Male Orgasmic Disorder, and erectile dysfunction. Suitably, the subject may suffer from sexual dysfunction (Female) Sexual Interest / Arousal Disorder (FSIAD). Suitably, the subject may suffer from Sexual Interest / Arousal Disorder (SIAD). Suitably, the subject may suffer from Female Orgasmic Disorder. Suitably, the subject may suffer from Orgasmic Disorder. Suitably, the subject may suffer from Hypoactive Sexual Desire Disorder (HSDD). Suitably, the subject may suffer from Male Orgasmic Disorder. Suitably, the subject may suffer from erectile dysfunction. SIAD refers to a loss of desire to sexual triggers or sexual cues that a subject previously experienced as arousing. A subject suffering from SIAD will experience this as distressing. Suitably, use of testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof according to the invention, may be for on-demand use. Suitably, on- demand use comprises administration prior to anticipated or planned sexual activity of the subject. Suitably, testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof, may be provided by non-invasive administration. The use of testosterone and oxytocin combined with rTMS and / or cognitive training may be useful in the treatment ofmood disorders, in particular depression and social anxiety. In a further embodiment, in accordance with the invention, a subject suffering from a mood disorder is selected from the group consisting of anxiety disorder, depressive disorder, and any combination thereof. In an embodiment the subject suffers from anxiety disorder. In another embodiment the subject suffers from depressive disorder, also known as depression. In a further embodiment, in accordance with the invention, a subject suffering from an anxiety disorder suffers from a social anxiety disorder. In a further embodiment, in accordance with the invention, a subject suffering from a depressive disorder suffers from major depressive disorder. The invention provides for testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from a cognitive disorder, sexual dysfunction, or mood disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and c. i. applying rTMS pulses to the brain of the subject; and / or ii. exposing the subject to cognitive training; thereby treating the subject suffering from the cognitive disorder, sexual dysfunction, ormood disorder, wherein one of a to c is performed at least before the othertwo of a to c. Hence, the invention provides for testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from a cognitive disorder, sexual dysfunction, or mood disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and c. i. applying rTMS pulses to the brain of the subject; and / or ii. exposing the subject to cognitive training; thereby treating the subject suffering from the cognitive disorder, sexual dysfunction, ormood disorder, wherein applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training is performed at least before administering an effective dosage oftestosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof, optionally wherein applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training is subsequently performed together or following administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof. The invention also provides fortestosterone and / or a functional analogue thereofand oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from a cognitive disorder, sexual dysfunction, or mood disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and c. i. applying rTMS pulses to the brain of the subject; and / or ii. exposing the subject to cognitive training; thereby treating the subject suffering from the cognitive disorder, sexual dysfunction, ormood disorder, wherein two of a to c are performed at least before the other one of a to c. Hence, the invention provides for testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from a cognitive disorder, sexual dysfunction, or mood disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and c. i. applying rTMS pulses to the brain of the subject; and / or ii. exposing the subject to cognitive training; thereby treating the subject suffering from the cognitive disorder, sexual dysfunction, ormood disorder, wherein administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof is performed at least before applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training, optionally wherein administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof is subsequently performed together or following applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training. The invention also provides fortestosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from a cognitive disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and c. i. applying rTMS pulses to the brain of the subject; and / or ii.exposing the subject to cognitive training; thereby treating the subject suffering from the cognitive disorder, wherein applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training is performed at least before administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof, optionally wherein applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training is subsequently performed together or following administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof. The invention also provides fortestosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from a sexual dysfunction, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and c. i. applying rTMS pulses to the brain of the subject; and / or ii.exposing the subject to cognitive training; thereby treating the subject suffering from the sexual dysfunction, wherein applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training is performed at least before administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof, optionally wherein applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training is subsequently performed together or following administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof. The invention also provides fortestosterone and / or a functional analogue thereofand oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from a sexual dysfunction, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and c. i. applying rTMS pulses to the brain of the subject; and / or ii.exposing the subject to cognitive training; thereby treating the subject suffering from the sexual dysfunction, wherein administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof is performed at least before applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training, optionally wherein administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof is subsequently performed together or following applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training. The invention also provides fortestosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from a mood disorder, the treatmentcomprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; and b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and c. i. applying rTMS pulses to the brain of the subject; and / or ii.exposing the subject to cognitive training; thereby treating the subject suffering from the mood disorder, wherein applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training is performed at least before administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof, optionally wherein applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training is subsequently performed together or following administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof. The invention also provides fortestosterone and / or a functional analogue thereofand oxytocin and / or a functional analogue thereof foruse in a treatment ofa subject suffering from a mood disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; and b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and c. i. applying rTMS pulses to the brain of the subject; and / or ii.exposing the subject to cognitive training; thereby treating the subject suffering from the mood disorder, wherein administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof is performed at least before applying rTMS pulses to the brain ofthe subject and / or exposing the subject to cognitive training, optionally wherein administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof is subsequently performed together or following applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training. The invention also provides fortestosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from an anxiety disorder, preferably a social anxiety disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; and b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and c. i. applying rTMS pulses to the brain ofthe subject; and / or ii.exposing the subject to cognitive training; thereby treating the subject suffering from the anxiety disorder, preferably the social anxiety disorder, wherein applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training is performed at least before administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof, optionally wherein applying rTMS pulses to the brain ofthe subject and / or exposing the subject to cognitive training is subsequently performed together or following administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof. The invention also provides fortestosterone and / or a functional analogue thereofand oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from an anxiety disorder, preferably a social anxiety disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; and b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and c. i. applying rTMS pulses to the brain of the subject; and / or ii.exposing the subject to cognitive training; thereby treating the subject suffering from the anxiety disorder, preferably the social anxiety disorder, wherein administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof is performed at least before applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training, optionally wherein administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof is subsequently performed together or following applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training. The invention also provides fortestosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in a treatment ofa subject suffering from a depressive disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; and b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and c. i. applying rTMS pulses to the brain of the subject; and / or ii.exposing the subject to cognitive training; thereby treating the subject suffering from the depressive disorder, wherein applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training is performed at least before administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof, optionally wherein applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training is subsequently performed together or following administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof. The invention also provides fortestosterone and / or a functional analogue thereofand oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from a depressive disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; and b. administering an effective dosage of oxytocin and / or a functional analogue thereof; and c. i. applying rTMS pulses to the brain of the subject; and / or ii.exposing the subject to cognitive training; thereby treating the subject suffering from the depressive disorder, wherein administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof is performed at least before applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training, optionally wherein administering an effective dosage of testosterone and / or a functional analogue thereof and administering an effective dosage of oxytocin and / or a functional analogue thereof is subsequently performed together or following applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training. The invention also provides fortestosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in a treatment of a subject suffering from a cognitive disorder, sexual dysfunction, or mood disorder, the treatment comprising: a. administering an effective dosage of testosterone and / or a functional analogue thereof; and b. administering an effective dosage of oxytocin and / or a functional analogue thereof; wherein the subject has been treated before the administering of the effective dosage of testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof such that cognitive function of the subject is improved. The invention also provides a method of selecting a subject suffering from a cognitive disorder, sexual dysfunction, or mood disorder having increased benefit of a treatment comprising administering testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof, the method comprising: a. determining cognitive function of the subject and / or an improvement of cognitive function of the subject compared to a previous point in time; b. selecting the subject for the treatment comprising administering testosterone and / or a functional analogue thereofand oxytocin and / ora functional analogue thereof ifthe subject has cognitive function in the top 80% of a general reference population, the top 70% of a general reference population, the top 60% of a general reference population, the top 50% of a general reference population, the top 40% of a general reference population, the top 30% of a general reference population, orthe top20% of a general reference population, and / or a signicant improvement of cognitive function compared to a previous point in time. The invention also provides a method ofselecting a subject suffering from a cognitive disorder, sexual dysfunction, ormood disorder having increased benefit ofa treatment comprising administering testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof, the method comprising: a. determining cognitive function of the subject and / or an improvement of cognitive function of the subject compared to a previous point in time; b. selecting the subject for the treatment comprising administering testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof if: i. the subject has cognitive function in the lowest 50% of a general reference population, the lowest 40% of a general reference population, the lowest 30% of a general reference population, or the lowest 20% of a general reference population, and / or a signicant improvement of cognitive function compared to a previous point in time; and / or. ii. the subject suffers cognitive dysfunction according to diagnostic criteria according to formal classification systems, such as the various versions of the DSM (i.e., a set of signs, symptoms, and 5 tests used to determine a person's diagnosis).

Claims

1. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in the treatment of a person suffering from a cognitive disorder, sexual dysfunction or mood disorder, where the treatment includes: a. administration of an effective dose of testosterone and / or a functional analogue thereof; b. administration of an effective dose of oxytocin and / or a functional analogue thereof; and ci the application of repetitive transcranial magnetic stimulation (rTMS) pulses on the brain of the person; and / or ii. expose the person to cognitive training; whereby the person suffering from the cognitive disorder, sexual dysfunction or mood disorder is being treated.

2. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with Claim 1, comprising carrying out one from a to with c of: a. administration of an effective dose of testosterone and / or a functional analogue thereof; b. administration of an effective dose of oxytocin and / or a functional analogue thereof; and to apply rTMS pulses to the person's brain; and / or ii. expose the person to cognitive training; at least before the other two from a to c.

3. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with claim 2, whereby carrying out one of a to c includes improving the person's cognitive function.

4. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with claim 1, comprising the application of rTMS pulses to the person's brain and / or exposing the person to cognitive training prior to the administration of an effective dose of testosterone and / or a functional analogue thereof and / or the administration of an effective dose of oxytocin and / or a functional analogue of them.

5. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with claim 1 or 4, whereby the application of rTMS pulses on the person's brain and / or exposing the person to cognitive training includes improving the person's cognitive function.

6. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with one of Claims 2 to 5, in which i. it is one of a through c; or ii. the application of rTMS pulses to the brain of the person and / or the exposing the person to cognitive training is further carried out in combination with respectively i. the other two from a to c; or ii. the administration of an effective dose testosterone and / or a functional analogue thereof and / or the administration of an effective dose oxytocin and / or a functional analogue thereof.

7. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with claim 1, comprising carrying out two from a to with c of: a. administration of an effective dose of testosterone and / or a functional analogue thereof; b. administration of an effective dose of oxytocin and / or a functional analogue thereof; and to apply rTMS pulses to the person's brain; and / or ii. expose the person to cognitive training; at least for the others from a to c.

8. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with one of Claims 1 to 7, in which each from a to and is performed 1-7 times per week for a period of 1-10 weeks, preferably 2-3 times a week for 5 weeks or longer.

9. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with one of Claims 2 to 7, in which i. one of a to and with c; or ii. the application of rTMS pulses to the brain of the person and / or the exposing the person to cognitive training 1-7 times per week is carried out for a period of 1-10 weeks, preferably 2-3 times per week for 5 weeks or longer.

10. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with one of Claims 1 to 9, whereby the application of rTMS pulses on the person's brain the application of rTMS pulses to the brain of the person includes, with a stimulus frequency, number of impulses and intensity that is sufficient to an electric field in the person's brain or increased neural activity in the to induce the person's brain, optionally in which the rTMS pulses are applied within a period of 3-6 or 4-5 hours after administration of testosterone and / or its functional analogue and / or within a period of 2 hours after administration of oxytocin and / or the functional analogue of them.

11. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with one of Claims 1 to 10, in which: a. the rTMS pulses are applied left, right, or bilaterally to the prefrontal cortex, including the dorsolateral prefrontal cortex (DLPFC) and / or inferior frontal gyrus (IFG); b. the rTMS pulses have a stimulation frequency of 1-100 Hz; and / or c. the applied rTMS pulses comprise high-frequency rTMS (Hz >5) over the left DLPFC and / or low-frequency rTMS (Hz <1) on the right DLPFC, and / or high-frequency rTMS directed at the judge IFG; and / or d. the applied rTMS pulses comprise high-frequency rTMS (Hz >5) over bilateral DLPFC; and / or e. the number of rTMS pulses is 100-3000; and / or f. the stimulus intensity of the applied rTMS is between 0.05 and 5 Tesla.

12. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with one of Claims 1 to 11, whereby the treatment of a person suffering from a cognitive disorder, sexual dysfunction or mood disorder improving cognitive function, improving the working memory, improving inhibitory function, improving cognitive includes flexibility and / or stopping or slowing the progression of memory impairment; and / or where the cognitive training includes the training of cognitive and / or executive functions, such as learning or practicing chess, learning or practicing a musical instrument and / or singing in a choir.

13. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with one of Claims 1 to 12, in which: a. the testosterone and / or the functional analogue thereof is administered in the form of a sublingual formulation, preferably in which the formulation contains cyclodextrin; and / or b. the testosterone and / or functional analogue thereof is administered in a total amount between 0.1-20 mg, preferably between 0.1-2 mg or 0.25-1 mg; and / or c. the person is a man and in which the testosterone and / or the functional analogue thereof is administered in a total amount between 0.5 and 20 mg, preferably between 1 and 10 mg; and / or d. in which, whereby the testosterone and / or the functional analogue thereof is formulated to after administration a peak level of free testosterone of 0.020 nmol / L or more for women and 0.4 to be delivered to the person's bloodstream to men in the bloodstream; and / or e. in which the functional testosterone analogue is dihydrotestosterone.

14. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with one of Claims 1 to 13, in which: a. the effective dose of oxytocin and / or its functional analogue is administered in a form that causes increased oxytocin levels 3-6 hours after administration of testosterone and / or the functional analogue; and / or b. whereby the effective dose of oxytocin and / or the functional analogue is administered intranasally administered, preferably 3-5 hours after administration of the testosterone and / or the functional analogous; and / or c. in which the effective dose of oxytocin and / or its functional analogue is administered in a total amount between 10-100 IU, preferably between 20-50 IU; and / or d. where the treatment involves the application of rTMS pulses to the brain of the person with a stimulus frequency, number of pulses and intensity sufficient to create an electric field in the person's brain or increased neural activity in the person's brain to induce involves, whereby the rTMS pulses are applied within a period of 4-5 hours after the administration of testosterone and / or its functional analogue, and / or within a period of 2 hours after the administration of oxytocin and / or its functional analogue, at preference whereby the administration of testosterone and / or its functional analogue takes place in the form of a sublingual formulation.

15. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with one of Claims 1 to 14, where the person suffers from: a cognitive impairment chosen from the group consisting of mild cognitive impairment, dementia and a combination thereof; and / or b. a sexual dysfunction chosen from the group consisting of: Sexual Interest / Arousal Disorder (FSIAD), Orgasmic Disorder, Hypoactive Sexual Desire Disorder (HSDD), erectile dysfunction and any combination of the aforementioned; and / or c. a mood disorder chosen from the group consisting of an anxiety disorder, a depressive disorder and a combination thereof; and / or d. an anxiety disorder chosen from the group consisting of social anxiety disorder; and / or e. a depressive disorder selected from the group consisting of major depressive disorder and depressive disorder 16. A treatment method for a person suffering from a cognitive disorder, sexual dysfunction or mood disorder, where the treatment includes: a. administration of an effective dose of testosterone and / or a functional analogue thereof; b. administration of an effective dose of oxytocin and / or a functional analogue thereof; and to apply rTMS pulses to the person's brain; and / or ii. expose the person to cognitive training.

17. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in the treatment of a person suffering from a cognitive disorder, where the treatment includes: a. administration of an effective dose of testosterone and / or a functional analogue thereof; b. administration of an effective dose of oxytocin and / or a functional analogue thereof; and to apply rTMS pulses to the person's brain; and / or ii. expose the person to cognitive training; in which one from a to c, preferably c, is performed before the other two from a to c, through which the person suffering from the cognitive disorder is treated.

18. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in the treatment of a person suffering from sexual dysfunction, whereby the treatment includes: a. administration of an effective dose of testosterone and / or a functional analogue thereof; b. administration of an effective dose of oxytocin and / or a functional analogue thereof; and to apply rTMS pulses to the person's brain; and / or ii. expose the person to cognitive training; through which the person suffering from the sexual dysfunction is treated.

19. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use pursuant to claim 18, where the cognitive training comprises: the automatic or unconsciously directing the person's attention to one or more positive stimuli, whereby the one or more positive stimuli are interpreted more positively than before the start of the cognitive training, preferably where one or more positive stimuli are an image of a include the person's partner.

20. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in the treatment of a person suffering from a mood disorder, where the treatment includes: a. administration of an effective dose of testosterone and / or a functional analogue thereof; and b. administration of an effective dose of oxytocin and / or a functional analogue thereof; and optional to apply rTMS pulses to the person's brain; and / or ii. expose the person to cognitive training; through which the person suffering from the mood disorder is treated.

21. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in the treatment of a person suffering from an anxiety disorder, at preference for a social anxiety disorder, where the treatment includes: a. administration of an effective dose of testosterone and / or a functional analogue thereof; and b. administration of an effective dose of oxytocin and / or a functional analogue thereof; and optional to apply rTMS pulses to the person's brain; and / or ii. expose the person to cognitive training; whereby the person suffering from the anxiety disorder, preferably social anxiety disorder, becomes treated.

22. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in the treatment of a person suffering from a depressive disorder, where the treatment includes: a. administration of an effective dose of testosterone and / or a functional analogue thereof; and b. administration of an effective dose of oxytocin and / or a functional analogue thereof; and optional to apply rTMS pulses to the person's brain; and / or ii. expose the person to cognitive training; through which the person suffering from the depressive disorder is treated.

23. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with one of Claims 20 to 22, whereby the Cognitive training includes: the automatic or unconscious directing of the person's attention on one or more positive stimuli, whereby the one or more positive stimuli become more positive interpreted differently than before the start of the cognitive training.

24. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in the treatment of a person suffering from a cognitive disorder, sexual dysfunction or mood disorder, where the treatment includes: a. administration of an effective dose of testosterone and / or a functional analogue thereof; and b. administration of an effective dose of oxytocin and / or a functional analogue thereof; in which the person prior to the administration of the effective dose of testosterone and / or a functional analog thereof and oxytocin and / or a functional analog thereof has been treated in such a way that the The person's cognitive function has improved.

25. A method for selecting a person suffering from a cognitive disorder, sexual dysfunction or mood disorder that benefits more from a treatment involving the administration of testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof, whereby the method comprises: a. determining the cognitive function of the person and / or an improvement of the cognitive function of the person in relation to an earlier point in time; b. selecting the person for the treatment involving the administration of testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof includes if the person's cognitive function is in the top 80% of a general reference population is located, like the top 70% of a general reference population, the top 5 60% of a general reference population, the top 50% of a general reference population, the top 40% of a general reference population, the top 30% of a general reference population or the top 20% of a general reference population, and / or a significant improvement in cognitive function compared to an earlier point in time.