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

[0001] Methods and means of treating mental disorders

[0002] Field of the invention

[0003] The invention relates to a combination of testosterone and oxytocin for administration to individuals for improvement of a cognitive disorder, sexual dysfunction, or mood 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 of the active ingredients, rTMS and / or cognitive training is further administered with the other of the active ingredients, rTMS and / or cognitive training.

[0004] Background of the invention

[0005] Mental disorders are characterized by a clinically significant disturbance in an individual’s 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).

[0006] 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, brainstimulation, and psychotherapy.

[0007] However, due to the high complexity of the human brain, its individual development during the lifespan of the 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 interindividual variability.

[0008] Hence, there remains a need for more effective and reliable treatment of mental disorders, in particular when assessed in view of a group of patients suffering from a specific mental disorder.

[0009] 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.

[0010] Summary of the invention

[0011] The current inventors provide a combination treatment of a subject suffering from a cognitive disorder, sexual dysfunction, or mood 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 of the disorder. Preferably, testosterone is administered sublingually and oxytocin intranasally. Preferably, testosterone and oxytocin are administered in a specific sequence in time.

[0012] 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.

[0013] Importantly, 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.

[0014] 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.

[0015] 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.

[0016] 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.

[0017] Herein, in the context of a 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 of the subject; and / or ii. exposing the subject to cognitive training.

[0018] 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.

[0019] 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 of a to c, preferably c, is performed at least before the othertwo of a to c, thereby treating the subject suffering from the cognitive disorder.

[0020] Herein is also 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 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.

[0021] 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.

[0022] 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 .

[0023] Also provided herein is 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 thereof and oxytocin and / or a functional analogue thereof if the 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, or the top 20% of a general reference population, and / or a significant 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, 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 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 significant 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 Diagnostic and Statistical Manual of Mental Disorders (DSM), preferably version DSM-5 or DSM-5-TR (i.e., a set of signs, symptoms, and tests used to determine a person's diagnosis).

[0024] Definitions

[0025] 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 or symptom. 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.

[0026] 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. In 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 or SHBG. A non-limiting example may be using a competitor of the testosterone binding site on SHBG.

[0027] As used herein, the term “cyclodextrin”, includes displacement enhancers such as polybetacyclodextrin, hydroxypropylbeta-cyclodextrin, and gamma cyclodextrin.

[0028] As used herein, the term “sublingual formulation”, refers to a formulation of an 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.

[0029] 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.

[0030] 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.

[0031] Description of the figures

[0032] Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which:

[0033] Figure 1 shows the results of a Virtual Reality Lateralized Approach Protocol (VR-LAP) for Enhancing Positive Mood in Midlife Women with Mild Mood Complaints. Increased Vigor-Activity scores across all sessions are shown, with the strongest effects observed in the combined VR + pharmacological condition. Effects persisted one day after exposure, suggesting short-term carryover.

[0034] Figure 2 shows the results of a VR-LAP for Enhancing Positive Mood in Midlife Women with Mild Mood Complaints. Reduced Tension-Anxiety scores across all sessions are shown, with the strongest effects observed in the combined VR + pharmacological condition. Effects persisted one day after exposure, suggesting short-term carryover.

[0035] Further details of the figures are disclosed in the Examples section below.

[0036] Detailed description of the invention

[0037] It is an object of the invention 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, 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.

[0038] 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.

[0039] 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 of a to c, preferably c, is performed at least before the othertwo of a to c, thereby treating the subject suffering from the cognitive disorder.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] Without 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 of the 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.

[0045] 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 matter changes 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.

[0046] 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 of the 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.

[0047] 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 of the subject. An even further improvement is achieved by at least applying one ortwo of the treatment modalities (i.e. testosterone, oxytocin, rTMS pulses, and cognitive training) priorto 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 of the subject also results in improved treatment effectiveness.

[0048] 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 of the subject. An even further improvement 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 of the 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), but may have the opposite effect on the “out-group” (relative to the patient). A patient’s partner who is the object of the patient’s 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 further may include a training task to get a positive interpretation.

[0049] In 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 subject’s 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 of the subject also results in improved treatment effectiveness.

[0050] 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, of testosterone 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 2.5-6 hours after sublingual administration) and oxytocin (e.g. from about 15 minutes to 90 minutes after intranasal administration) overlap.

[0051] Testosterone is known to increase the brain's sensitivity to cues associated with behavior driven by social interaction. Testosterone (17-0-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.

[0052] 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, for example 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.

[0053] 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.

[0054] Preferably, the subject according to the disclosure is a human subject.

[0055] 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.

[0056] 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.

[0057] Without being bound by theory, administration of testosterone 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 of the brain to stimuli and therefore for example, an increasing effect on cognitive function.

[0058] Suitably, the total amount of testosterone and / or a functional analogue thereof, such as dihydrotestosterone, that is provided to a subject in need thereof may 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.

[0059] Suitably, testosterone and / or a functional analogue thereof may 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).

[0060] Preferably, administration of testosterone and / or a functional analogue thereof, such as dihydrotestosterone, is via oral administration, preferably by sublingual administration.

[0061] 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.

[0062] 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 of the subject.

[0063] 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 of the testosterone and / or a 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.

[0064] 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 of certain 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 specificity, but has widespread effects on intrinsic brain functioning. Studies using functional magnetic resonance imaging (fMRI) with oxytocin administration reveal a specific set of social brain regions through which oxytocin influences human behavior.

[0065] 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 of the brain, improving cognitive (executive) functions such as short- and long-term memory. Intranasal 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 behavior and the like use dosages between 20 to 50 IE of oxytocin, typically 24 IE. Behavioral and neural effects of administered dosages are around 15 to 90 minutes after administration.

[0066] 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, of about 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 dosing 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.

[0067] Suitably, administration of sublingual testosterone and / or a functional analogue thereof may be followed by administering of intranasal oxytocin and / or a functional analogue thereof during a time window of about 3 to 6 hours after the peak concentration of testosterone in the blood circulation. Intranasal 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.

[0068] 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, or less) after the 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.

[0069] A preferred route of administration of oxytocin is as a nasal spray, e.g. with a dose of 4 IE per spray. The skilled person may appropriately use other suitable forms of oxytocin and / or further 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 thereof and oxytocin and / or a functional analogue thereof may 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.

[0070] 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 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.

[0071] 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.

[0072] 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).

[0073] 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 of rTMS 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.

[0074] Patients suffering from the disorders as described herein may benefit from multiple treatments.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] Suitably, the exposure to cognitive training may be an immediate subsequent exposure.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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).

[0084] 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.

[0085] 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.

[0086] 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 of the cognitive training. Suitably, the cognitive training may further comprise learning not to automatically or subconsciously focus attention towards one or more negative stimuli.

[0087] Virtual reality is a simulated experience that employs 3D near-eye displays, and optionally pose tracking, to give the user an immersive feel of a virtual world. Standard virtual reality systems may use either virtual reality headsets or multi-projected environments to generate some realistic images, sounds, and other sensations that simulate a user's physical presence in a virtual environment. A person using virtual reality equipment is able to e.g. look around the artificial world, move around in it, and interact with virtual features or items. The effect is commonly created by virtual reality headsets consisting of a head-mounted display with a small screen in front of the eyes but can also be created through specially designed rooms with multiple large screens. Virtual reality typically incorporates auditory and video feedback but may also allow other types of sensory and force feedback through haptic technology.

[0088] It was found that virtual reality can be advantageously employed in the methods and uses of the present invention for providing cognitive training.

[0089] Suitably, cognitive training according to the invention may comprise virtual reality or virtual reality training. Suitably, cognitive training may comprise using virtual reality or virtual reality training. Suitably, treatment of a subject according to the invention comprising exposing the subject to cognitive training may comprise exposing the subject to cognitive training using virtual reality.

[0090] Suitably, the virtual reality or the virtual reality training may comprise using a virtual reality headset.

[0091] Suitably, the virtual reality or the virtual reality training may comprise providing information, preferably one or more positive stimuli, only to the right visual field of the subject, thereby stimulating the left hemisphere of the subject. Suitably, the virtual reality orthe virtual reality training may comprise providing information, preferably one or more positive stimuli, only to the left visual field of the subject, thereby stimulating the right hemisphere of the subject. Suitably, the virtual reality or the virtual reality training may comprise providing information, preferably one or more positive stimuli, only to the right eye of the subject, thereby stimulating the left hemisphere of the subject. Suitably, the virtual reality or the virtual reality training may comprise providing information, preferably one or more positive stimuli, only to the left eye of the subject, thereby stimulating the right hemisphere of the subject.

[0092] Suitably, the virtual reality orthe virtual reality training may comprise reducing inhibitory control of the prefrontal cortex. Suitably, the virtual reality orthe virtual reality training may comprise providing a concurrent cognitive load task. Suitably, the concurrent cognitive load task may be provided centrally, to both visual fields, or to both eyes of the subject.

[0093] 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, wherein the cognitive training comprises virtual reality. Suitably, the cognitive training may further comprise learning not to automatically or subconsciously focus attention towards one or more negative stimuli, wherein the cognitive training comprises virtual reality.

[0094] 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 of the cognitive training, wherein the cognitive training comprises virtual reality. Suitably, the cognitive training may further comprise learning not to automatically or subconsciously focus attention towards one or more negative stimuli, wherein the cognitive training comprises virtual reality.

[0095] 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.

[0096] 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.

[0097] 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, other symptoms 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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 of the cervix and uterus, and expansion of the 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 of sexual satisfaction of a 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.

[0102] 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.

[0103] 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.

[0104] The use of testosterone and oxytocin combined with rTMS and / or cognitive training may be useful in the treatment of mood 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.

[0105] In a further embodiment, in accordance with the invention, a subject suffering from an anxiety disorder suffers from a social anxiety disorder.

[0106] In a further embodiment, in accordance with the invention, a subject suffering from a depressive disorder suffers from major depressive disorder.

[0107] 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, or mood disorder, wherein one of a to c is performed at least before the other two of a to c.

[0108] 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, or 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.

[0109] The invention also 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, or mood 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, or 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 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.

[0110] The invention also 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, 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.

[0111] The invention also 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 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.

[0112] The invention also 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 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.

[0113] The invention also 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 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 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.

[0114] The invention also 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 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 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.

[0115] The invention also 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 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 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.

[0116] The invention also 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 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 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 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.

[0117] The invention also 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 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.

[0118] The invention also 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; 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.

[0119] 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 thereof and oxytocin and / or a functional analogue thereof if the 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, or the top 20% of a general reference population, and / or a significant improvement of cognitive function compared to a previous point in time.

[0120] 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 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 significant 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 tests used to determine a person's diagnosis).

[0121] Examples

[0122] The Examples follow serve to illustrate the invention and are not meant in any way to limit the invention.

[0123] Example 1

[0124] Virtual Reality Lateralized Approach Protocol (VR-LAP) for Enhancing Positive Mood in Midlife Women with Mild Mood Complaints

[0125] Introduction

[0126] The present study explored an innovative neuropsychological method designed to selectively activate the left limbic system, which is associated with approach behavior and positive affect. The protocol, termed Virtual Reality Lateralized Approach Protocol (VR-LAP), exposes participants to positive emotional stimuli (e.g., social interactions, rewarding imagery) restricted to the right visual field, thereby stimulating the left hemisphere. To reduce inhibitory control of the left prefrontal cortex (PFC) — which can dampen positive arousal — a concurrent cognitive load task (simple arithmetic problems) was presented centrally in the VR environment.

[0127] Equipment

[0128] The study employed the Meta Quest 3 VR headset (Meta Platforms Inc.), priced around €550. Specifications: o Resolution: 2064 x 2208 pixels per eye (high visual clarity for lateralized presentation) o Field of View: 110° o Wireless operation and integrated spatial tracking o Compatible with Unity-based custom VR applications for visual field control o Lightweight (515 g) for comfortable 10-minute exposures

[0129] This headset allows precise control of visual field segmentation and real-time task integration (e.g., math tasks projected in the central visual field).

[0130] Participants and Design

[0131] Two female participants (ages 32 and 38) with mild mood complaints (according to the Beck Depression Inventory II1with a score of 13 and 15 respectively) took part in a repeated-measures within-subject design.

[0132] Three experimental sessions were conducted on alternate days:

[0133] 1 . VR exposure only (positive right-field stimuli + arithmetic task)

[0134] 2. Pharmacological intervention only (0.5 mg sublingual testosterone followed by 24 IU intranasal oxytocin, 4 hours later)

[0135] 3. Combined intervention (VR-LAP exposure following testosterone and oxytocin administration)

[0136] Mood was assessed using two Profile of Mood States (POMS)2subscales: Tension-Anxiety and Vigor-Activity, before and 15 minutes after experimental manipulations.

[0137] Results Both participants showed reduced Tension-Anxiety and increased Vigor-Activity scores across all sessions, with the strongest effects observed in the combined VR + pharmacological condition. Effects persisted one day after exposure, suggesting short-term carryover. The combined VR + pharmacological condition showed a more than additive effect over the VR or pharmacological only conditions separately. The results are visually presented in Figures 1 and 2.

[0138] Discussion

[0139] The findings suggest that selective right-field exposure to positive stimuli, combined with cognitive load to reduce PFC inhibition, effectively enhances positive mood and reduces anxiety-related tension. The Meta Quest 3 headset proved suitable for controlled lateralized presentation and integration of concurrent cognitive tasks. The additive effect of oxytocin and testosterone may have further amplified approach-related activation and emotional openness.

[0140] Conclusion

[0141] This small-scale pilot indicates that VR-LAP, particularly when combined with oxytocin and testosterone, can substantially enhance vigor and reduce anxiety in women with mild mood complaints. The results support the hypothesis that lateralized VR exposure targeting the left hemisphere can modulate mood through limbic activation and reduced prefrontal inhibition.

[0142] References

[0143] 1. Beck, A. T., Steer, R. A., & Brown, G. K. (1998). Beck Depression Inventory-ll: Nederlandse vertaling en bewerking [Dutch translation and adaptation by P. A. van der Does], Harcourt Test Publishers.

[0144] 2. MACKENZIE, B. (2001) Profile of Mood States (POMS) [WWW] Available from: https: / / www.brianmac.co.uk / poms.htm [Accessed 9 / 11 / 2025]

Claims

Claims1 . 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.

2. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with claim 1 , comprising performing one of a to c of: 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; at least before the other two of 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, wherein performing the one of a to c comprises improving cognitive function of the subject.

4. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with claim 1 , comprising applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training before administering an effective dosage of testosterone and / or a functional analogue thereof and / or administering an effective dosage of oxytocin and / or a functional analogue thereof.

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, wherein applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training comprises improving cognitive function of the subject.

6. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with any one of claims 2 to 5, wherein i. the one of a to c; or ii. applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training is further performed in combination with respectively i. the other two of a to c; or ii. administering an effective dosage of testosterone and / or a functional analogue thereof and / or administering an effective dosage of 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 performing two of a to c of: 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; at least before the other one of a to c.

8. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with any one of claims 1 to 7, wherein each of a to c is performed 1-7 times a week during a period of 1-10 weeks, preferably 2-3 times a week for 5 weeks or more.

9. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with any one of claims 2 to 7, wherein i. the one of a to c; or ii. applying rTMS pulses to the brain of the subject and / or exposing the subject to cognitive training is performed 1-7 times a week during a period of 1-10 weeks, preferably 2-3 times a week for 5 weeks or more.

10. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with any one of claims 1 to 9, wherein applying rTMS pulses to the brain of the subject comprises applying 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, optionally wherein the rTMS pulses are applied within a period of 3-6 or 4-5 hours after administering the testosterone and / or the functional analogue thereof and / or within a period of 2 hours after the administration of oxytocin and / or functional analogue thereof.11 . Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with any one of claims 1 to 10, wherein: a. the rTMS pulses are applied left, right or bilaterally applied to the prefrontal cortex, including the dorsolateral prefrontal cortex (DLPFC) and / or inferior frontal gyrus (IFG); b. the rTMS pulses have a stimuli frequency of 1-100 HZ; and / or c. the rTMS pulses applied 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; and / or d. the rTMS pulses applied include high-frequent 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 any one of claims 1 to 11 , wherein the treatment of a subject suffering from a cognitive disorder, sexual dysfunction, or mood disorder comprises improving cognitive function, improving working memory, improving inhibition function, improving cognitive flexibility and / or halting or delaying progression of memory impairment; and / or wherein the cognitive training comprises training cognitive and / or executive functions, such as learning or practicing chess, learning or practicing a musical instrument and / or singing in a choir; and / or wherein the cognitive training comprises using virtual reality.

13. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with any one of claims 1 to 12, wherein: a. the testosterone and / or functional analogue thereof is administered in the form of a sublingual formulation, preferably wherein the formulation comprises cyclodextrin; and / or b. the testosterone and / or functional analogue thereof is administered in a total amount in the range of 0.1-20 mg, preferably in the range of 0.1-2 mg or 0.25-1 mg; and / or c. the subject is a male subject and wherein the testosterone and / or functional analogue thereof is administered in a total amount in the range of 0.5-20 mg, preferably in the range of 1-10 mg; and / or d. wherein, whereby the testosterone and / or functional analogue thereof 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 for males in the blood circulation of the subject; and / or e. wherein the functional analogue of testosterone is dihydrotestosterone.

14. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with any one of claims 1 to 13, wherein: a. the effective dosage of the oxytocin and / or functional analogue thereof is administered in a form providing increased oxytocin levels 3-6 hours after administration of the testosterone and / or functional analogue; and / or b. wherein the effective dosage of oxytocin and / or functional analogue thereof is administered intranasally, which is preferably administered 3-5 hours after administration of the testosterone and / or functional analogue; and / or c. wherein the effective dosage of oxytocin and / or functional analogue thereof is administered in a total amount in the range of 10-100 IE, preferably in the range of 20-50 IE; and / or d. wherein the treatment comprises applying 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 an increased neural activity in the brain of the subject, wherein the rTMS pulses are applied within a period of 4-5 hours after the administration of testosterone and / or functional analogue thereof, and / or within a period of 2 hours after the administration of oxytocin and / or functional analogue thereof, preferably wherein the administration of testosterone and / or functional analogue thereof is 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 any one of claims 1 to 14, wherein the subject suffers from: a. a cognitive disorder selected from the group consisting of mild cognitive impairment, dementia, and any combination thereof; and / or b. a sexual dysfunction selected 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 selected from the group consisting of an anxiety disorder, a depressive disorder, and any combination thereof; and / or d. an anxiety disorder selected 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 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.

17. 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 of a to c, preferably c, is performed before the other two of a to c, thereby treating the subject suffering from the cognitive disorder.

18. 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.

19. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with claim 18, wherein the cognitive training comprises: 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 ore more positive stimuli comprise an image of a partner of the subject and / orwherein exposing the subject to cognitive training comprises using virtual reality.

20. 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.21 . 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.

22. 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.

23. Testosterone and / or a functional analogue thereof and oxytocin and / or a functional analogue thereof for use in accordance with any one of claims 20 to 22, wherein the cognitive training comprises: 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 exposing the subject to cognitive training comprises using virtual reality.

24. 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.

25. 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 thereof and oxytocin and / or a functional analogue thereof if the subject has cognitive function in the top 80% of a general reference population, such as 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, or the top 20% of a general reference population, and / or a significant improvement of cognitive function compared to a previous point in time.

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