1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine for the prevention or treatment of emotional blunting

Abstract

The present invention relates to therapeutic uses of 1-[2-(2,4-dimethylphenylsulfanyl]-phenyl]piperazine, including preventing, alleviating, or treating apathy in a patient.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to European Patent Application No. 20167895.0 filed on April 3, 2020 and European Patent Application No. 20185247.2 filed on July 10, 2020, the contents of each of which are incorporated herein by reference in their entirety.

[0002] Incorporation by Reference All patents, patent applications, and patent publications cited herein are incorporated herein by reference in their entirety to more fully describe the state of the art known to those skilled in the art as of the date of the invention described herein.

[0003] The present invention relates to the therapeutic use of 1 - [2 - (2,4 - dimethylphenylsulfanyl) - phenyl] piperazine.

Background Art

[0004] CNS disorders and conditions such as major depressive disorder ("MDD"), major depressive episode ("MDE"), schizophrenia, or post - traumatic stress disorder ("PTSD") are recurrent diseases that cause disorders and are very prevalent worldwide. Among these patients, some experience limitations in emotions, which are a normal part of daily life such as the ability to feel happiness or worry.

[0005] MDD is a disease that causes a severe recurrent disorder that can be treated with selective serotonin reuptake inhibitors ("SSRI") and serotonin - norepinephrine reuptake inhibitors ("SNRI"). However, approximately 50% of all patients show only a partial response to these therapies with respect to the resolution of depressive symptoms (Rush et al., Am. J. Psychiatry (2006), 163, 1905 - 1917, which is incorporated herein by reference in its entirety).

[0006] In addition, approximately 50% of all MDD patients treated with SSRIs or SNRIs report some degree of emotional blunting, which may be drug-related (Goodwin et al., Journal of Affective Disorders, (2017), 221, 31-35; Bolling and Kohlenberg, (2004), 73, 380-385 (these are incorporated herein by reference in their entirety)). Emotional blunting is a condition characterized by a limitation of emotions that clinically manifests as emotional disinterest and detachment, reduced responsiveness, decreased motivation, and apathy (Price J, Cole V, Goodwin GM., Br.J. Psychiatry, (2009), 195(3), 211-217 (these are incorporated herein by reference in their entirety)). Individuals with emotional blunting report a feeling of numbness, an inability to laugh or cry, an inability to enjoy things they previously enjoyed, a feeling of reduced empathy, and a feeling of apathy towards others. They also often complain about a loss of inspiration and passion for creative activities, as well as a diminished sense of social responsibility and concern for others.

[0007] MDD, with a global prevalence of 15%, is treated with commonly used antidepressants such as SSRIs or SNRIs as both primary and secondary treatment. SSRIs have long been preferred by physicians for the treatment of many central nervous system ("CNS") disorders, including depression and anxiety, due to their effectiveness and favorable safety profile compared to previous generations of CNS drugs, i.e., so-called tricyclic antidepressants. Known adverse events from the treatment of MDD with antidepressants such as SSRIs and SNRIs include changes in sleep patterns, changes in sexual function, headaches, and weight gain. A less commonly investigated side effect in clinical trials is emotional blunting experienced by patients taking these medications, including antipsychotics used to treat schizophrenia.

[0008] Currently, most available antipsychotic medications improve the positive symptoms of schizophrenia but fail to adequately address negative symptoms and cognitive impairment. This leaves a significant unmet need for treatment options for a subpopulation of up to 35–40% of schizophrenic patients who suffer from persistent negative symptoms (Mucci A. et al., Schizophr. Res., (2017), 186, 19–28; Rabinowitz J. et al., Schizophr. Res., (2013), 150(2–3), 339–342 (these are incorporated herein by reference in their entirety)). In 50-60% of schizophrenia patients who are considered clinically stable in terms of positive symptoms, there are also negative symptoms that are not adequately addressed, and this is the main cause of functional impairment in this group of patients (Bobes J. et al., J. Clin. Psychiatry, (2010), 71(3), 280-286 (the entire article is incorporated herein by reference)).

[0009] Furthermore, most available antipsychotics are known to cause serious side effects, such as extrapyramidal symptoms ("EPS"). Therefore, the search for central nervous system-acting drugs with improved efficacy against negative and cognitive symptoms and a favorable side effect profile is crucial for developing better treatment options, particularly for patients with persistent negative symptoms, persistent and marked negative symptoms, and / or cognitive impairment in schizophrenia. Such novel treatments may also prove beneficial for non-schizophrenic patients with negative symptoms and cognitive impairment.

[0010] Emotional blunting is clinically significant because it affects patients' functioning in their work, social, and family lives and hinders full functional recovery. For example, patients experiencing emotional blunting may avoid or ignore responsibility, which can result in financial or work / school problems and a decline in the quality of family life or parenting. Therefore, emotional blunting is a burden for patients and negatively impacts their health-related quality of life and daily functioning (Price et al., 2009 (above)). Functional impairments and residual symptoms such as emotional blunting are significant because studies have shown that patients with functional MDD in remission or stable schizophrenia are at higher risk of relapse (Bobes J. et al., 2010 (above)).

[0011] Emotional blunting and anhedonia are associated with dysfunction of central dopaminergic, mesolimbic, and mesocortical reward circuit pathways (Pan et al., Curr. Pharm. Des. (2017), 23, 2065-2072; Sternat and Katzman, Neuropsychiatr. Dis. Treat. (2016), 12, 2149-2164 (these are incorporated herein by reference in their entirety)). Anhedonia is a condition characterized by a reduced capacity to experience pleasure, and is a common symptom of MDD, reported in approximately 75% of patients (Franken et al., J. Affect. Disord. 2007), 99, 83-89 (the entire report is incorporated herein by reference); Sternat and Katzman, 2016 (above)), and is part of the negative symptoms in patients with schizophrenia (Mucci A. et al., Schizophrenia Research, (2017), 186, 19-28; Rabinowitz J. et al., Schizophr Res., (2013) 150(2-3), 339-342 (the entire reports are incorporated herein by reference, respectively)). Anhedonia is dependent on hedonic mood, and a low hedonic mood indicates a reduced capacity to experience pleasure and increases the likelihood of anhedonia (Franken et al., 2007 (above)). Anhenaghasidd and impaired reward circuit pathways are associated with poor prognosis and suboptimal treatment response (Buckner et al., Psychiatry Res., (2008), 159, 25-30; Uher et al., Psychol Med (2012), 42, 967-980 (these are incorporated herein by reference in their entirety)).

[0012] Affective blunting overlaps phenotypically with anhedonia, but the two conditions are not identical (Cao et al., Prog. Neuropsyhopharmacol. Biol. Psychiatry, (2019), 92, 109-117; Esperidiao-Antonio et al., Int Rev Psychiatry (2017), 29, 293-307; Loas et al., Compr. Psychiatry (1994), 35, 366-372 (each incorporated herein by reference)). Cao et al. (Cao et al., Frontiers in Psychiatry, (2019), 10, 17 (each incorporated herein by reference)) describe anhedonia as a common and persistent distressing phenomenon in treated adults with MDD. Relatively few antidepressants have been evaluated for their effectiveness against anhedonia in MDD. Cao et al. (above) also re-examined the results showing that vortioxetine significantly improved anhedonia, as assessed by marked improvement from baseline in endpoints on the Smith-Hamilton Pleasure Scale ("SHAPS") and the Montgomery Asberg Depression Rating Scale ("MADRS") anhedonia factor scores. Improvements in the SHAPS and MADRS anhedonia factors correlated with improvements in general function (i.e., the Sheehan Disability Scale ("SDS")) and quality of life (i.e., the World Health Organization Happiness Index ("WHO-5")), and in some patients, affective blunting and anhedonia showed phenotypic overlap.

[0013] Anhedonia is associated with a lack of positive emotions, while emotional blunting is a state of lack or blunting of all emotions, both positive and negative. It is not possible to predict whether medications that alleviate anhedonia will also alleviate emotional blunting. The term “anhedonia” primarily refers to the inability to experience pleasure (Rizvi SJ, Pizzagalli DA, Sproule BA, Kennedy SH, Neuroscience and Biobehavioral Reviews, (2016), 65, 21-35 (the whole is incorporated herein by reference)). Anhedonia is a central diagnostic feature of major depressive episodes, and patients with anhedonia may accept a diagnosis of MDD even if the “depressed mood” criterion is not accepted (American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders: DSM-5. Washington, DC: American Psychiatric Association (the whole is incorporated herein by reference)).

[0014] Patients with emotional blunting very frequently experience anhedonia, but the blunted emotions are not limited to pleasure, but include several other emotions, including negative emotions. On the contrary, patients with anhedonia can experience negative emotions very well, and their perception is amplified rather than dulled. This may explain why some antidepressants, including SSRIs, have shown effectiveness in treating anhedonia during major depressive episodes, but at the same time, they also show the ability to induce emotional blunting. Indeed, many antidepressants can improve the inability to experience pleasure and reduce the intensity of negative emotions. However, the same antidepressants can induce emotional blunting, reducing the ability to experience physiologically negative emotions (e.g., crying at a funeral; feeling sad when something bad happens), while simultaneously "stabilizing" positive emotions, flattening them to a range that is better but not normal than the intensity experienced during depression. Thus, patients may experience improvement in anhedonia. In other words, while patients are no longer plagued by excessive negative emotions or unable to experience joy, they become emotionally blunted, for example, with reduced creativity, a diminished ability to engage with things for enjoyment, and a reduced response to life events.

[0015] As mentioned above, emotional blunting may be associated with antidepressant treatment with SSRIs or SNRIs. Emotional blunting is usually associated with SSRI administration, and the likelihood of developing the syndrome increases with higher doses (Sansone and Sansone, Psychiatry (Edgmont) (2010), 7, 14-18 (the whole is incorporated herein by reference)), and in some cases, it may be resolved by reducing the dose. In other cases, the condition does not resolve until the SSRI is discontinued. Emotional blunting has been proposed to be related to serotonergic effects in the frontal lobe and / or serotonergic modulation of the mesebral dopaminergic system protruding into the prefrontal cortex. By broadly enhancing serotonergic transmission, SSRI drugs activate gamma-aminobutyric acid ("GABA") interneurons, thereby suppressing noradrenergic and dopaminergic input (Blier, Int. J. Neuropsychopharmacol., (2014), 17, 997-1008 (the whole article is incorporated herein by reference)).

[0016] This phenomenon of emotional blunting has been described in various ways, such as emotional indifference, reduced emotional response or sensitivity, or a feeling of emotional numbness. In a study by Price et al., patients generally described this phenomenon as feeling emotionally “blunted,” “numb,” “flattened,” or completely “blocked,” as well as “blank” or “flat.” Generally, emotional blunting often occurs in conjunction with other symptoms such as decreased thinking ability, difficulty concentrating, and decreased libido.

[0017] Emotional blunting is a significant burden and negatively impacts quality of life and daily functioning (Price J, Cole V, Goodwin GM., Br.J. Psychiatry, (2009), 195(3), 211-217 (the whole is incorporated herein by reference)). Emotional blunting is a real functional consequence for patients' social, family, and work lives. Some patients describe experiencing reduced love, affection, and pride for their partners and family, reduced sympathy and empathy in social interactions, and reduced concern and interest in their responsibilities at work. A significant proportion of patients experience a feeling of “not caring at all” about things that were once important to them, and this effect was attributed to antidepressant treatment. A recent study by Goodwin et al. found that nearly half (46%) of patients taking SSRIs or SNRIs may experience emotional blunting. (Goodwin GM, Price J, Bodinat CD, J. Affect. Disord. (2017), 221, 31-35 (the whole is incorporated herein by reference)). That is, even during remission, emotions are restricted across the full range of emotions that a patient would normally experience. Emotional blunting has also been recognized as a common reason for MDD patients to discontinue treatment (Rosenblat et al., J Affect. Disord. (2019), 243, 116-120 (the whole is incorporated herein by reference)).

[0018] Another explanation for the phenomenon of emotional blunting is that it is a symptom of depressive mood, and that its association with SSRIs and related medications did not result in complete remission of the symptoms, rather than being merely a side effect of the therapy itself (Goodwin et al., 2017 (above)). This is likely due to the neurobiological and phenotypic overlap between emotional blunting and other features of MDD, particularly anhedonia (Cao et al., Prog Neuropsyhopharmacol Biol.Psychiatry, 2019; Esperidiao-Antonio et al., 2017; Loas et al., 1994; Pan et al., 2017; Sternat and Katzman, 2016 (each incorporated herein in its entirety by reference)). However, while emotional blunting describes a clinical condition characterized by a lack of both positive and negative emotions, anhedonia is characterized by a lack of only positive emotions (Sternat and Katzman, 2016 (see above)).

[0019] This may explain why SSRIs may be effective against anhedonia symptoms during major depressive episodes (i.e., when the patient can no longer experience excessive negative emotions or pleasure), but affective blunting symptoms may persist (e.g., the patient still experiences an inability to enjoy and participate in normally pleasurable activities and exhibits a reduced response to life events). Affective blunting and anhedonia are associated with dysfunction in central dopaminergic, mesolimbic, and mesocortical reward pathways (Pan et al., 2017 (above); Sternat and Katzman, 2016 (above)).

[0020] Patients suffering from emotional blunting may also exhibit a persistent inability to experience positive emotions (e.g., happiness, contentment, or affection), a significantly reduced interest in or participation in important activities, and, in some cases, feelings of isolation or alienation from others. Other related subjective experiences that may be reported by patients feeling emotionally numb may include feelings of being emotionally dead, blocked out, empty and / or empty, and a complete lack of emotion. These subjective experiences are associated with a degree of lack of concern for one's own and others' well-being.

[0021] Severe emotional disturbances are likely to be associated with a general decline in functional capacity, a reduced quality of remission from depressive symptoms, and a more negative perception of the condition, and may be grounds for discontinuing treatment (Goodwin GM, Price J, Bodinat CD, Laredo J., J. Affect. Disord. (2017), 221, 31-35 (the entire work is incorporated herein by reference)).

[0022] Emotional numbness, as described above, can be conceptualized not only as a reaction seen as an adverse event in medical treatment using, for example, SSRIs or SNRIs, but also as part of the symptoms of certain CNS disorders or disorders, for example, as part of the onset of depression, or even as a biopsychological response to extreme emotional or physical trauma. Thus, emotional numbness or blunting may be observed in patients who have experienced extreme emotional or physical trauma, for example, patients diagnosed with PTSD. Patients with PTSD typically present to initial medical attention with unexplained physical and / or psychological symptoms, including sleep disturbances, night sweats, fatigue, and impaired memory or concentration (Walter A., ​​Pharmacotherapy for Post-traumatic Stress Disorder In Combat Veterans P T. (2012); 37(1): 32-38 (the whole of which is incorporated herein by reference)). The U.S. Food and Drug Administration ("FDA") has approved paroxetine and sertraline for the treatment of PTSD. Some treatment guidelines recommend fluoxetine and venlafaxine, along with other antidepressants, as first-line treatments, on par with intensive cognitive behavioral therapy ("CBT") (Toll WA, Barbui C, Ommeren, JAMA, (2013); 310:477-478 (the entire article is incorporated herein by reference)). Others consider intensive CBT to have better evidence and suggest antidepressants only when therapy has failed or is unavailable, or in cases of severe depression (Bajor LA, Ticlea AN, Osser DN, Harv. Rev. Psychiatry (2011), 19:240-258 (the entire article is incorporated herein by reference); Toll WA, Barbui C, Ommeren, JAMA (2013), 310:477-478 (see above)). This reflects several negative randomized clinical trials ("RCTs") using SSRIs, showing a small to moderate effect size compared to trauma-focused ("TF")-CBT. For example, nalmefene, an opioid receptor antagonist used to treat alcohol dependence, is known to be studied to establish its effects on emotional blunting.Between 1988 and 1990, nalmefene was administered in an open-label pilot study to treat veterans diagnosed with PTSD. The published pilot study reported the administration of low doses of the drug, gradually increasing from 1 milligram twice daily to a maximum of 200 milligrams twice daily. Based on the study results, nalmefene was observed to significantly reduce, and in some cases alleviate, symptoms of emotional blunting, and to promote the veterans' ability to experience a range of normal human responses, including empathy, love, concern, and caring for others. This drug has also been shown to significantly improve all major symptoms of PTSD, including nightmares, intrusive thoughts, and flashbacks; inability to engage with topics dealing with combat experiences without developing emotional distress or behavioral avoidance symptoms; dissociative amnesia; distrust of others; and hyperarousal and reactivity associated with traumatic events (Diagnostic Statistical Manual-5. American Psychiatric Association, pub, 2013 (the entire manual is incorporated herein by reference)).

[0023] A study by Oxford University showed that 46–71% of antidepressant users experienced emotional blunting during treatment. According to this study, the antidepressants most commonly associated with emotional blunting fall into one of three classes: 1. SSRIs such as Lexapro (escitalopram), Prozac (fluoxetine), Zoloft (sertraline), and Paxil (paroxetine) (Goodwin GM, Price J, Bodinat CD, Laredo J. Emotional blunting with antidepressant treatments: A survey among depressed patients. J. Affect. Disord. 2017;221:31-35 (the entire article is incorporated herein by reference)); 2. SNRIs such as Cymbalta (duloxetine), Pristiq (desvenlafaxine), and Effexor XR (venlafaxine); and 3. Tricyclic and tetracyclic antidepressants such as Elavil (amitriptyline) and Remeron.

[0024] The proportion of people experiencing emotional blunting was similar across the three drug classes, but varied. Approximately 33% experienced emotional blunting while taking Wellbutrin (bupropion) (Goodwin GM, Price J, Bodinat CD, Laredo J., J Affect Disord. (2017), 221:31-35 (see above)), and 75% experienced the same effect with Cymbalta.

[0025] Another study concluded that agomelatine was associated with a lower frequency of emotional blunting than escitalopram. In fact, about 28% of patients taking agomelatine felt their emotional intensity was reduced compared to about 60% of patients taking escitalopram, and about 16% of patients taking agomelatine felt that things they cared about before becoming ill were no longer important compared to about 53% of patients taking escitalopram (p=0.024) (Christian de Bodinatet al., Journal of Neuropsychopharmacology, (2013), 16(10), 2219-2234 (the whole article is incorporated herein by reference)).

[0026] Wellbutrin (bupropion) itself differs from other antidepressants in that it is a dopamine and norepinephrine reuptake inhibitor. Unlike others, Wellbutrin (bupropion) does not target the serotonin transporter ("SERT") (Patel K, Allen S, Haque MN, Angelescu I, Baumeister D, Tracy DK., Ther. Adv. Psychopharmacol. (2016), 6(2), 99-144 (the whole of which is incorporated herein by reference)). This may suggest that serotonin inhibition may be one of the main causes of emotional blunting with antidepressants such as SSRIs or SNRIs.

[0027] However, since emotional blunting has not been reported in all patients taking antidepressants, it has been difficult to identify the exact reasons for emotional blunting. There are even questions as to whether blunting is a side effect of antidepressant treatment, or perhaps a partial impairment of the drug itself, i.e., leading to residual depressive symptoms.

[0028] Considering that the incidence of emotional blunting in patients treated with Wellbutrin (bupropion) is low, the research suggests that the effect of antidepressants on SERT plays a major role in emotional blunting, but still, it is considered unlikely that a single hormone is the sole cause of this phenomenon. Furthermore, it is suggested that emotional blunting is better understood as an identified symptom rather than a side effect of the drug (Jones JD, Butterfield LC, Song W, et al., J Neuropsychiatry Clin. Neurosci. (2015), 27(3), 213 - 8 (incorporated herein by reference in its entirety)); that is, when antidepressants relieve depression, the potential symptoms of emotional blunting are revealed rather than being caused.

[0029] The data presented herein show that vortioxetine brings relief to approximately half of the patients experiencing emotional blunting, can significantly reduce the symptoms of emotional blunting in all patients participating in the study, the effect is already observed one week after treatment, and the magnitude of the effect increases in the following seven weeks of treatment. This effect should be expected regardless of whether emotional blunting is a direct result of medical treatment with antidepressants or whether medical treatment with antidepressants reveals the potential symptoms to be treated. A similar effect can be expected in the treatment of emotional blunting in patients experiencing, for example, part of the negative symptoms in schizophrenia or psychosis, or the exacerbation of negative symptoms due to treatment with drugs for the treatment of schizophrenia or psychosis such as antipsychotics.

[0030] Excessive dopamine neurotransmission is associated with schizophrenia. Antipsychotics, also known as neuroleptics, are a class of compounds that have a high affinity for several subtypes of dopamine receptors. Due to the chemical structures of various antipsychotics, they can bind to dopamine receptors without triggering the postsynaptic response to which dopamine normally binds. Because neuroleptics have the ability to block dopamine receptors without opening ion channels and generating action potentials, they can be administered to patients with schizophrenia to help reduce excessive levels of dopamine and alleviate the positive symptoms of the disorder. Conventional typical and atypical antipsychotics have demonstrated clinical efficacy in treating positive symptoms such as hallucinations and delusions, but are often ineffective and may even worsen negative symptoms such as emotional blunting and social withdrawal, as well as cognitive function. The inability to treat these latter symptoms can contribute to the social dysfunction associated with schizophrenia. The dysfunction of multiple neurotransmitter systems in schizophrenia suggests that drugs selectively targeting a single neurotransmitter pathway are unlikely to meet all the therapeutic needs of this heterogeneous disorder (Peng Li et al. Current Topics in Medicinal Chemistry, (2016), 16, 3385-3403 (the entire article is incorporated herein by reference)).

[0031] International Publication No. 2003 / 029232 (which is incorporated herein by reference in its entirety) and International Publication No. 2007 / 144005 (which is incorporated herein by reference in its entirety) disclose the compound 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]-piperazine and its pharmaceutically acceptable salts. Vortioxetine (1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]-piperazine) is a multimodal antidepressant that acts by mediated modulation of receptor activity and inhibition of serotonin transporters. As of July 1, 2020, vortioxetine is approved in more than 80 countries worldwide for the treatment of major depressive disorder, including by the FDA in September 2013 and the European Commission on December 18, 2013. In clinical development programs, vortioxetine has been shown to be effective and safe, and is well-tolerated in adults and elderly patients with MDD for both short-term treatment and long-term maintenance therapy. The approved therapeutic dose range for vortioxetine in adults is 5–20 mg / day.

[0032] Vortioxetine is a multimodal antidepressant that shares some common characteristics with SSRIs and SNRIs. However, because vortioxetine is also a multimodal antidepressant that exhibits a different pattern of effects and side effects than SSRIs and SNRIs, a clinical trial named COMPLETE, trial number 17797A (EudraCT number 2017-004829-33 (incorporated in its entirety by reference)), sponsored by H. Lundbeck A / S, was launched to evaluate the effect of vortioxetine on emotional blunting. In clinicaltrial.gov, trial number NCT03835715 (incorporated in its entirety by reference), the abstract summarizes the objective of the trial as: "This study will evaluate the efficacy of variable-dose vortioxetine on emotional function in patients with major depressive disorder who are inadequately responding to SSRIs / SNRIs." The EudraCT trial registration cites the same objective in the formal name of the trial.

[0033] Goodwin et al. (Goodwin et al., Journal of Affective Disorders, (2017), 211, 31-35) and Jonathan Price et al. (Jonathan Price et al., Journal of Affective Disorders, (2012), 140, 66-74) (their entirety incorporated herein by reference) have reported on the use of the Oxford Questionnaire for Affective Disorders.

[0034] Emmanuelle Corruble et al. (International Journal of Neuropsychopharmacology, (2013), 16(10), 2219-2234 (the entire document is incorporated herein by reference)) disclose the Oxford Questionnaire for establishing emotional side effects in patients after treatment with escitalopram and agomelatine in the treatment of emotional blunting. The article states that agomelatine is associated with a lower frequency of emotional blunting than escitalopram. In fact, 28% of patients taking agomelatine compared 60% of patients taking escitalopram felt their emotional intensity was reduced, and 16% of patients taking agomelatine compared 53% of patients taking escitalopram felt that things they cared about before becoming ill were no longer important (p=0.024). The mechanism by which vortioxetine is effective in adults with MDD experiencing emotional blunting is not fully understood. However, the effect of vortioxetine on emotional blunting in other patients suffering from CNS disorders or conditions is expected to be similarly beneficial; such CNS disorders or conditions may be, for example, psychiatric or mood disorders. Theoretical reasons for why compounds that are 5-HT1A agonists and / or 5-HT3 antagonists are expected to be useful in treating cognitive impairment have been reported, and clinical evidence has been validated, for example, by the International Publication No. 2009 / 062517 pamphlet (which is incorporated herein by reference in its entirety). T. Sumiyoshi in Am. J. Psych., 158, 1722-1725, 2001 (which is incorporated herein by reference in its entirety) reports a study in which patients took typical antipsychotic drugs such as haloperidol, sulpiride, and pimozide, all lacking 5-HT1A activity, in combination with placebo or tandospirone, a 5-HT1A agonist. Patients who took tandospirone in addition to antipsychotics showed improvement in cognitive abilities, while patients who took a placebo did not.Similarly, atypical antipsychotics such as clozapine, which are also 5-HT1A agonists, enhance cognitive function in patients with schizophrenia, while typical antipsychotics such as haloperidol, which do not possess 5-HT1A activity, do not enhance cognitive function in patients with schizophrenia (Y. Chung, Brain Res., (2004), 1023, 54-63 (the entire text is incorporated herein by reference)). A randomized, double-blind, crossover trial in healthy men demonstrated that the 5-HT3 antagonist allosetron reduces scopolamine-induced impairments in verbal and spatial memory and sustained attention (Preston, Recent Advances in the Treatment of Neurodegenerative Disorders and Cognitive Function, 1994, (eds.) Racagni and Langer, Basel Karger, pp. 89-93 (the entire text is incorporated herein by reference)). International Publication Brochure No. 2009 / 062517 (above), for Example 5, shows that the 1-[2-(2,4-dimethylphenyl-sulfanyl)-phenyl]piperazine compound caused an increase in extracellular levels of acetylcholine in the prefrontal cortex and ventral hippocampus of rats, and Example 6 shows that they improved contextual memory in rats. However, no data have been reported on the effect of vortioxetine on emotional blunting. [Overview of the project]

[0035] The present invention relates to a structure for use in treating, preventing, or alleviating emotional blunting. [ka] This relates to 1-[2-(2,4-dimethylphenyl-sulfanyl)-phenyl]piperazine and its pharmaceutically acceptable salts.

[0036] Oral dosage forms, particularly tablets, are often preferred by patients and physicians because they are easy to administer and have good subsequent compliance. In the case of tablets, the active ingredient is preferably crystalline. In some embodiments, the present invention relates to crystalline compounds.

[0037] International Publication No. 2007 / 144005 (which is incorporated herein by reference in its entirety) discloses several pharmaceutically acceptable salts and solvates of 1-[2-(2,4-dimethylphenyl-sulfanyl)-phenyl]piperazine. A preferred salt of 1-[2-(2,4-dimethylphenyl-sulfanyl)-phenyl]piperazine is the hydrobromide salt; 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]-piperazine HBr. International Publication No. 2007 / 144005 (above) further discloses the X-ray powder diffraction ("XRPD") reflectances of further salts used in the present invention. The following table summarizes the main XRPD reflectances of some of the compounds used in the present invention.

[0038] [Table 1]

[0039] The crystalline compounds used herein may exist in multiple forms, i.e., they may exist in polymorphic forms. Polymorphic forms exist when a compound can crystallize in multiple forms. The present invention is intended to encompass all such polymorphic forms, either as pure compounds or as mixtures thereof.

[0040] In some embodiments, the present invention uses a purified form of the compound. The term “purified form” is intended to indicate that the compound essentially does not contain other compounds or other forms of the same compound.

[0041] The mechanism of action of vortioxetine is thought to be related to the direct modulation of serotonin receptor activity and the inhibition of the serotonin (5-HT) transporter (SERT). Nonclinical data indicate that vortioxetine is a 5-HT3, 5-HT7, and 5-HT1D receptor antagonist, a 5-HT1B receptor partial agonist, and a 5-HT1A receptor agonist and SERT inhibitor, resulting in the modulation of neurotransmission in several systems. This multimodal activity is thought to be a factor in the antidepressant and anxiolytic-like effects observed with vortioxetine in animal studies, as well as improvements in cognitive function, learning, and memory.

[0042] The present invention relates to the prevention, treatment, or mitigation of signs and symptoms of emotional blunting in patients. Such patients may or may not have been diagnosed with one or more CNS disorders or conditions, and may or may not have a history of signs and symptoms of emotional blunting resulting from drug administration. In some aspects of the present invention, the CNS disorders or conditions are selected from the group of mental disorders such as psychosis, schizophrenia, schizoaffective disorder, schizophrenia-like disorder, catatonia, and delusional disorder; mood disorders such as bipolar disorder, cyclothymic disorder, major depressive disorder, dysthymia, and premenstrual dysphoric disorder; and substance use disorders.

[0043] In some aspects of the present invention, the one or more CNS disorders or conditions are PTSD, depression (including MDD and major depressive episodes ("MDE")), cognitive impairment, schizophrenia, psychosis, Parkinson's disease, autism, vascular dementia, and multiple system atrophy, and the patient has experienced an inadequate response to the treatment, and as a result of such treatment, there has been a report or diagnosis of adverse events, symptoms or signs of emotional blunting.

[0044] The present invention also relates to the prevention or treatment of emotional blunting in patients receiving treatment for one or more CNS diseases or conditions, wherein the emotional blunting is a result of an inadequate response to the treatment for one or more CNS diseases or conditions.

[0045] The present invention also relates to the prevention or treatment of emotional blunting in patients receiving medical treatment for one or more CNS diseases or conditions, wherein the emotional blunting is a result of the medical treatment for one or more CNS diseases or conditions.

[0046] The present invention further relates to the prevention, treatment, or mitigation of signs and symptoms of emotional blunting in patients receiving treatment for one or more CNS disorders or conditions; including PTSD, depression (including MDD and MDE), cognitive impairment, schizophrenia, psychosis, Parkinson's disease, autism, vascular dementia, and multiple system atrophy, wherein the patients have experienced an inadequate response to such treatment and have reported or been diagnosed with adverse events, symptoms or signs of emotional blunting as a result of such treatment.

[0047] The present invention further relates to the prevention, treatment, or mitigation of signs and symptoms of emotional blunting in patients treated for one or more diseases or conditions; PTSD, depression, cognitive impairment, schizophrenia, psychosis, Parkinson's disease, autism, vascular dementia, and multiple system atrophy, wherein the patients have experienced an inadequate response to the treatment for one or more diseases or conditions, and as a result of such treatment, an adverse event, a report or diagnosis of symptoms or signs of emotional blunting has been made.

[0048] The present invention further relates to the prevention, treatment, or mitigation of signs and symptoms of emotional blunting in patients diagnosed with and / or treated for one or more diseases or conditions: PTSD, depression, cognitive impairment, schizophrenia, psychosis, Parkinson's disease, autism, vascular dementia, and multiple system atrophy, wherein the patients have experienced an inadequate response to the treatment for one or more diseases or conditions, and as a result of such treatment, an adverse event, a report or diagnosis of symptoms or signs of emotional blunting has been made.

[0049] The present invention further relates to the prevention of signs and symptoms of emotional blunting in patients diagnosed with and / or treated for one or more diseases or conditions: PTSD, depression, cognitive impairment, schizophrenia, psychosis, Parkinson's disease, autism, vascular dementia, and multiple system atrophy, wherein the patients have experienced an inadequate response to the treatment for one or more diseases or conditions, and as a result of such treatment, an adverse event, a report or diagnosis of symptoms or signs of emotional blunting has been made.

[0050] The present invention further relates to the treatment or mitigation of signs and symptoms of emotional blunting in patients diagnosed with and / or treated for one or more diseases or conditions: PTSD, depression, cognitive impairment, schizophrenia, psychosis, Parkinson's disease, autism, vascular dementia, and multiple system atrophy, wherein the patients have experienced an inadequate response to the treatment for one or more diseases or conditions, and as a result of such treatment, adverse events, symptoms or signs of emotional blunting have been reported or diagnosed.

[0051] The present invention further relates to the prevention, treatment, or mitigation of signs and symptoms of emotional blunting in patients diagnosed with but not treated for one or more diseases or conditions: PTSD, depression, cognitive impairment, schizophrenia, psychosis, Parkinson's disease, autism, vascular dementia, and multiple system atrophy, wherein the patients have experienced an inadequate response to the treatment of one or more diseases or conditions, and as a result of such treatment, an adverse event, a report or diagnosis of symptoms or signs of emotional blunting has been made.

[0052] The present invention further relates to the prevention of signs and symptoms of emotional blunting in patients diagnosed with but not treated for one or more diseases or conditions: PTSD, depression, cognitive impairment, schizophrenia, psychosis, Parkinson's disease, autism, vascular dementia, and multiple system atrophy, wherein the patients have experienced an inadequate response to the treatment of one or more diseases or conditions, and as a result of such treatment, adverse events, symptoms or signs of emotional blunting have been reported or diagnosed.

[0053] The present invention further relates to the treatment or mitigation of signs and symptoms of emotional blunting in patients diagnosed with but not treated for one or more diseases or conditions: PTSD, depression, cognitive impairment, schizophrenia, psychosis, Parkinson's disease, autism, vascular dementia, and multiple system atrophy, wherein the patients have experienced an inadequate response to the treatment of one or more diseases or conditions, and as a result of such treatment, adverse events, symptoms or signs of emotional blunting have been reported or diagnosed.

[0054] The present invention further relates to the prevention, treatment, or reduction of signs and symptoms of emotional blunting in patients receiving treatment for mental disorders such as schizophrenia, psychosis, schizoaffective disorder, schizophrenia-like disorder, catatonia, and delusional disorder; mood disorders such as bipolar disorder, cyclothymic disorder, major depressive disorder, dysthymia, and premenstrual dysphoric disorder; and substance use disorders.

[0055] The present invention further relates to the prevention, treatment, or reduction of signs and symptoms of emotional blunting in patients receiving treatment for CNS disorders, which are mental disorders such as psychosis, schizophrenia, schizoaffective disorder, schizophrenia-like disorder, catatonia, and delusional disorder.

[0056] The present invention further relates to the prevention, treatment, or reduction of signs and symptoms of emotional blunting in patients receiving treatment for CNS disorders, which are mood disorders such as bipolar disorder, cyclothymic disorder, major depressive disorder, dysthymia, and premenstrual dysphoric disorder.

[0057] The present invention further relates to the prevention, treatment, or mitigation of signs and symptoms of emotional blunting in patients who have a substance use disorder or are being treated for a CNS disorder associated with a substance use disorder.

[0058] This application will be described with reference to the following drawings, which are provided for illustrative purposes only and are not intended to be limiting. [Brief explanation of the drawing]

[0059] [Figure 1]Figure 1 shows a schematic diagram of the tests described in Assays I-XI; the results are disclosed in Examples 1-12. [Figure 2] Figure 2 shows a baseline overview of the total scores (FAS, MMRM) on the Oxford Depression Scale ("ODQ") ((Copyright) Oxford University Innovation Limited, 2011) at the end of weeks 1, 4, and 8 of the study, reflecting the values ​​listed in Table 3. [Figure 3] Figure 3 shows the baseline scores for the total score of the ODQ ((Copyright) Oxford University Innovation Limited, 2011), demonstrating that the scores follow a normal distribution. [Figure 4] Figure 4 is a graph visualizing the baseline score of the MEI total score, showing that the score follows a normal distribution. [Figure 5] Figure 5 summarizes the clinical assessment of emotional blunting and its partial correlation and mediation analysis; *** indicates p<0.0001. [Figure 6] Figure 6 shows that improvements in motivation and energy, as assessed using MEI, were already substantial and significant from week 4 onwards in all subdomains: cognitive and mental energy, social motivation, and physical energy; *** indicates p<0.0001. [Figure 7] Figure 7 shows that mediation analysis further indicates that 63.4% of the change in the total SDS score explained by the change in the total ODQ ((copyright) Oxford University Innovation Limited, 2011) was due to the direct effect of the improvement in ODQ ((copyright) Oxford University Innovation Limited, 2011) after switching to vortioxetine, which could not be explained by the improvement in depressive symptoms (MADRS) (which explains 36.6% of the impact on the total SDS score). [Modes for carrying out the invention]

[0060] Detailed description of the invention The inventors have found that 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine, which exhibits a combination of SERT inhibition, 5-HT3 antagonism, and 5-HT1A agonism, is useful for preventing and treating emotional blunting in patients with CNS disorders and / or patients taking one or more medications for the treatment of CNS disorders.

[0061] Accordingly, the present invention provides a method for the prevention, treatment, or reduction of emotional blunting associated with one or more CNS disorders or conditions, the method comprising administering a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]-piperazine or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0062] In some embodiments, the present invention provides a method for the prevention, treatment, or reduction of emotional blunting associated with one or more CNS disorders or conditions, the method comprising administering a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]-piperazine or a pharmaceutically acceptable salt thereof to a patient in need thereof, the said administration of a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]-piperazine or a pharmaceutically acceptable salt thereof is provided as monotherapy or in combination with other agents for the prevention or treatment of one or more CNS disorders or conditions.

[0063] The present invention further relates to a method for preventing or treating emotional blunting or its signs and symptoms in a patient, the method comprising administering to a patient in need a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0064] The present invention further relates to a method for preventing or treating emotional blunting in a patient, wherein the patient has experienced emotional blunting or has a history of signs and symptoms of emotional blunting resulting from an inadequate response to a drug, and the method comprises administering a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to the patient in need, wherein the drug causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0065] The present invention also relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting in a patient. The present invention further relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting in a patient, wherein the patient has experienced emotional blunting or has a medical history of signs and symptoms of emotional blunting resulting from the administration of a drug, and the drug causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0066] Emotional blunting observed in patients who are proposed to take 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, either as monotherapy or in combination with other pharmaceutical agents for the treatment of one or more CNS disorders or conditions, may be observed in connection with the administration of an appropriate dose of the agent for the treatment of one or more CNS disorders or conditions, the appropriate dose of the agent being the dose indicated on the label of the agent. In some cases, the agent for the treatment of one or more CNS disorders or conditions is an antidepressant, an antipsychotic, or an agent for the treatment of psychosis or schizophrenia. In some aspects of the present invention, monotherapy with 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof requires discontinuation of any previously administered antidepressants, such as SSRIs or SNRIs, before the monotherapy is initiated.

[0067] Accordingly, in some aspects of the present invention, monotherapy with 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine is an alternative to previous monotherapy with antidepressants that enhance serotonergic transmission. In some aspects of the present invention, monotherapy with 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine is a first therapeutic means for the treatment of CNS diseases or disorders.

[0068] In some embodiments of the present invention, the combination of 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine with another agent for the treatment of one or more CNS diseases or disorders involves administering 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine simultaneously with (or together with) the administration of the other agent. Such “other agent” may be an agent that reduces dopaminergic transmission, or other agents used for the treatment of CNS diseases or disorders. In some embodiments, such “other agent” may be an antipsychotic agent.

[0069] SSRIs are associated with weaker effects on anhedonia compared to drugs that promote 5-HT-mediated cognitive and emotional blunting, as well as the release of NE and DA (Dale E, Bang-Andersen B, Sanchez C. Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs. Biochem Pharmacol. 2015;95(2):81-97; Gardier AM, Lepoul E, Trouvin JH, Chanut E, Dessalles MC, Jacquot C. Changes in dopamine metabolism in rat forebrain regions after cessation of long-term fluoxetine treatment: relationship with brain concentrations of fluoxetine and norfluoxetine. Life Sci. 1994;54:151-156; Lane RM. Restoration of positive mood states in major depression as a potential drug development target.J.Psychopharmacol.2014;28(6):527-535 (each of which is incorporated herein by reference in its entirety).Long-term use of SSRIs is known to reduce NE transmission (Szabo ST, de Montigny C, Blier P. Progressive attenuation of the firing activity of locus coeruleus noradrenergic neurons by sustained administration of selective serotonin reuptake inhibitors. Int J Neuropsychopharmacol. 2000;3(1):1-11; Kawahara Y, Kawahara H, Kaneko F, ​​Tanaka M. Long-term administration of citalopram reduces basal and stress-induced extracellular noradrenaline levels in rat brain. Psychopharmacology (Berl). 2007;194:73-81 (these entire works are incorporated herein by reference)).

[0070] In animal studies, vortioxetine increased extracellular levels of 5-HT, DA, and NE in both the medial prefrontal cortex and ventral hippocampus (Mork A, Pehrson A, Brennum LT, Nielsen SM, Zhong H, Lassen AB, et al. Pharmacological effects of Lu AA21004: a novel multimodal compound for the treatment of Major Depressive Disorder. J Pharmacol Exp Ther. 2012;340(3):666-675; Bang-Andersen B, Ruhland T, Jorgensen M, Smith G, Frederiksen K, Jensen KG, et al. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]-piperazine(Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder.J.Med.Chem.2011;54:3206-3221 (each of which is incorporated herein by reference in its entirety). Vortioxetine exhibits low potency in functional assays of NE and DA transporter inhibition. However, its effects on NE and DA levels are likely exerted indirectly, possibly through receptor modulation. For example, many interneurons in the brain are regulated by 5-HT3 receptors, and when blocked, this can lead to increases in 5-HT, DA, NE, acetylcholine, and histamine (D'Agostino A, English CD, Rey JA. Vortioxetine (Brintellix): a new serotonergic antidepressant. P T.2015;40(1):36-40 (each of which is incorporated herein by reference in its entirety)).

[0071] Vortioxetine is a multimodal antidepressant that shares some common characteristics with SSRIs and SNRIs. However, because vortioxetine is a multimodal antidepressant that also exhibits different patterns of effects and side effects than SSRIs and SNRIs, a clinical trial named COMPLETE, trial number 17797A (EudraCT number 2017-004829-33 (above)), sponsored by H. Lundbeck A / S, was launched to evaluate the effect of vortioxetine on emotional blunting. The abstract of the clinicaltrial.gov trial number NCT 03835715 (above) summarizes the objective of the trial as: "This study will evaluate the efficacy of variable-dose vortioxetine on emotional function in patients with major depressive disorder who are inadequately responding to SSRIs / SNRIs." The EudraCT trial registration cites the same objective in the full name of the trial.

[0072] Using the results of this study, we evaluated the efficacy of vortioxetine 10-20 mg / day to prevent and / or treat emotional blunting in MDD patients who are experiencing an inadequate response to SSRIs / SNRIs in their current depressive episode and who wish to switch to an alternative antidepressant. Such an inadequate response may be judged in the form of a reported or diagnosed response and may include all symptoms of depression, including symptoms or signs of emotional blunting.

[0073] Surprisingly, it was found that in patients who had previously reported effects, for example, by answering questions from the principal investigator in accordance with the ODQ ((Copyright) Oxford University Innovation Limited, 2011), emotional blunting could be significantly improved, i.e., completely reduced or eliminated.

[0074] The immediate reduction or elimination of this emotional blunting was observed during the first week of treatment with vortioxetine (10 mg) and became even more pronounced after eight weeks of treatment. Approximately 50% of patients were freed from the perception of emotional blunting. Significant effects (nominal p<0.05) were observed at all efficacy measures and trial endpoints (primary and secondary) at all assessment points for emotional blunting as assessed by ODQ ((copyright) Oxford University Innovation Limited, 2011), function as assessed by SDS, cognitive ability as assessed by the Digital Symbol Substitution Test ("DSST"), motivation and energy as assessed by the Motivation and Energy Inventory ("MEI") test, and depressive symptoms as assessed by MADRS. Correlations were observed between the reduction of emotional blunting and improvements in overall function (work, family, social) and motivation and energy (mental, social, physical). Furthermore, resolution of depressive symptoms was observed in approximately 47%. In line with the established profile of vortioxetine, its safety and tolerability were reported.

[0075] In extensive assessments of schizophrenia symptoms, negative symptoms recurred as separate factors, independent of positive symptoms, confusion, and affective symptoms including depression and anxiety. Additional research focusing on the underlying structure of negative symptoms themselves suggests that this symptom domain is not one-dimensional. The most reliable factors emerging among negative symptoms include reduced expressiveness (typically accompanied by symptoms of reduced facial expression, vocal expressiveness, and verbal expression) and factors that produce anhedonia and antisocialization (consisting of symptoms of anhedonia, diminished interest, and reduced social engagement) (Blanchard JJ, Cohen AS. The structure of negative symptoms within schizophrenia: implications for assessment. Schizophr Bull. 2006;32:238-245 (the whole work is incorporated herein by reference)). All widely used assessment and classification tools for negative symptoms include blunted or restricted emotions, such as the Scale for Assessment of Negative Symptoms ("SANS"), the Clinical Assessment Interview for Negative Symptoms ("CAINS"), and the Brief Negative Symptom Scale ("BNSS"). Blunted emotions can be thought to have three elements: (1) reduced facial expression; (2) reduced expressive gestures and other body language; and (3) reduced control of speaking volume, pitch, and speed. Blunt emotions should be distinguished from flat emotions, which represent the extreme end of the blunted range.

[0076] Emotional blunting can be seen in several disorders other than schizophrenia, including, for example, Parkinson's disease, depression, autism, vascular dementia, and multiple system atrophy. In the context of schizophrenia, antipsychotic drugs can induce this symptom, complicating the assessment of blunted emotions (Constantino JN, Gruber CP, Davis S, Hayes S, Passanante N, Przybeck T. The factor structure of autistic traits. J. Child Psychol. Psychiatry. 2004;45:719-726; Fetoni V, Soliveri P, Monza D, Testa D, Girotti F. Affective symptoms in multiple system atrophy and Parkinson's disease: response to levodopa therapy. J. Neurol. Neurosurg. Psychiatry. 1999;66:541-544; Tremeau F, Malaspina D, Duval F, et al. Facial expressiveness in patients with schizophrenia compared to depressed patients and nonpatient comparison). subjects.Am.J.Psychiatry.2005;162:92-101;Jouvent R,Le Houezec J,Payan C,et al.Dimensional assessment of onset of action of antidepressants: a comparative study of moclobemide vs.clomipramine in depressed patients with blunted affect and psychomotor retardation.Psychiatry Res.1998;79(3):267-275;Robertson JM, Tanguay PE, L'ecuyer S, Sims A, Waltrip C.Domains of social communication handicap in autism spectrum disorder. J.Am.Acad.Child Adolesc.Psychiatry. 1999;38:738-745; Sultzer DL, Levin HS, Mahler ME, High WM, Cummings JL.A. Comparison of psychiatric symptoms in vascular dementia and Alzheimer's disease. Am.J.Psychiatry. 1993;150:1806-1812 (these entire works are incorporated herein by reference).

[0077] Prevention, treatment, or reduction of signs and symptoms of emotional blunting according to the present invention may include daily administration of the compound of the present invention. This may include once-daily administration, twice-daily administration, or more frequently administration.

[0078] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine compound used in the present invention is a hydrobromide salt.

[0079] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine compound used in the present invention is, for example, a β-type hydrobromide salt.

[0080] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine compound used in the present invention is a hydrobromide salt, and a suitable tablet may consist of the following components:

[0081] [Table 2]

[0082] In particular, tablets may consist of the following ingredients:

[0083] [Table 3]

[0084] For example, tablets containing different amounts of the active compound, corresponding to 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, or 80 mg of free base, can be obtained by selecting an appropriate amount of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine compound in combination with a tablet of appropriate size. Preferred concentrations of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine HBr salt are about 5 mg, about 10 mg, or about 20 mg per tablet. Preferred concentration of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine HBr salt is about 5 mg per tablet. Preferred concentration of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine HBr salt is about 10 mg per tablet. The preferred concentration of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine HBr salt is approximately 20 mg per tablet. The preferred frequency of administration of tablets containing approximately 5 mg, approximately 10 mg, or approximately 20 mg of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or any pharmaceutically acceptable salt thereof is once daily. Patients starting with approximately 5 mg daily may increase the concentration to approximately 10 mg or approximately 20 mg daily. Patients starting with approximately 10 mg daily may increase the concentration to approximately 20 mg daily or decrease the concentration to approximately 10 mg daily. The therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof may be, for example, about 5 mg, about 10 mg, or about 20 mg of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine per day.

[0085] In some embodiments, the present invention relates to a method for preventing or treating emotional blunting or its signs and symptoms in a patient, the method comprising administering to a patient in need a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the present invention relates to a method for preventing or treating emotional blunting or its signs and symptoms in a patient experiencing signs and symptoms of emotional blunting, the method comprising administering to a patient in need a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the method for preventing or treating emotional blunting or its signs and symptoms in a patient is such that the patient has experienced or has a history of experiencing signs and symptoms of emotional blunting, and the agent causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or any pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the method for preventing or treating emotional blunting or signs and symptoms thereof in a patient is a method in which the patient has experienced emotional blunting or has a medical history of signs and symptoms of emotional blunting in connection with the administration of a drug, and the drug causing signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, the method for preventing or treating emotional blunting or signs and symptoms thereof in a patient is a method in which the patient has experienced emotional blunting or has a medical history of signs and symptoms of emotional blunting resulting from the administration of a drug, and the drug causing signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or any pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the method for preventing or treating emotional blunting or signs and symptoms thereof in a patient is a method in which the patient has experienced emotional blunting or has a history of signs and symptoms of emotional blunting resulting from the administration of an appropriate dose of a drug, wherein the drug causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the method for preventing or treating emotional blunting or signs and symptoms thereof in a patient is a method in which the patient has experienced emotional blunting or has a history of signs and symptoms of emotional blunting resulting from an inadequate response to medical treatment, and the agent causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or any pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the method for preventing or treating emotional blunting or signs and symptoms thereof in a patient is a method in which the patient has experienced emotional blunting or has a history of signs and symptoms of emotional blunting resulting from an inadequate response to medical treatment for a CNS disorder or disorder, and the agent causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or any pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the method for preventing or treating emotional blunting or its signs and symptoms in a patient is a method in which the patient has a medical history of exhibiting signs and symptoms of emotional blunting associated with a CNS disease or disorder, or the medical treatment of one or more CNS diseases or disorders, and the agent causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, and the method comprises the following steps: i) A step in which a practicing physician or doctor evaluates the patient, 1) Evaluation of the patient's medical history regarding signs and symptoms of emotional blunting; 2) Assessment of current signs or symptoms of emotional blunting; and / or 3) A step including an assessment of the risk that the patient will develop or worsen signs and / or symptoms of emotional blunting.

[0094] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting or its signs and symptoms in patients.

[0095] In some embodiments, the present invention relates to the use for preventing or treating emotional blunting or its signs and symptoms in patients experiencing signs and symptoms of emotional blunting.

[0096] In some embodiments, the present invention relates to the use for preventing or treating emotional blunting or its signs and symptoms in a patient, wherein the patient has experienced or has a history of experiencing signs and symptoms of emotional blunting, and the agent causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or any pharmaceutically acceptable salt thereof.

[0097] In some embodiments, the present invention relates to the use for preventing or treating emotional blunting or its signs and symptoms in a patient, wherein the patient has experienced emotional blunting or has a medical history of signs and symptoms of emotional blunting in connection with the administration of the agent, and the agent causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or any pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the present invention relates to the use for preventing or treating emotional blunting in a patient, wherein the patient has experienced emotional blunting or has a medical history of signs and symptoms of emotional blunting resulting from the administration of the drug, and the drug causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or any pharmaceutically acceptable salt thereof.

[0099] In some embodiments, the present invention relates to the use for preventing or treating emotional blunting in a patient, wherein the patient has experienced emotional blunting or has a history of signs and symptoms of emotional blunting resulting from the administration of an agent for treating one or more CNS disorders or conditions, and the agent causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or any pharmaceutically acceptable salt thereof.

[0100] In some embodiments, the present invention relates to the use for preventing or treating emotional blunting in a patient, wherein the patient has experienced emotional blunting or has a history of signs and symptoms of emotional blunting resulting from the administration of the drug in an appropriate dose, and the drug causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or any pharmaceutically acceptable salt thereof.

[0101] In some embodiments, the present invention relates to the use for preventing or treating emotional blunting in a patient, wherein the patient has a medical history of exhibiting signs and symptoms of emotional blunting associated with a CNS disease or disorder or one or more CNS medical treatments, and the agent causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, and the method comprises the following steps: i) The step of evaluating the patient by a practicing physician or doctor, 1) Evaluation of the patient's medical history regarding signs and symptoms of emotional blunting; 2) Assessment of current signs or symptoms of emotional blunting; and 3) A step including an assessment of the risk that the patient will develop or worsen signs and / or symptoms of emotional blunting.

[0102] In some embodiments, the appropriate dose of the drug is the dose indicated on the label of the drug. In some embodiments, the method for use in the prevention or treatment of emotional blunting according to the present invention or 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof means the drug or an appropriate dose thereof for the treatment of one or more CNS diseases or disorders, and the appropriate dose of the drug that is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine (-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine) or a pharmaceutically acceptable salt thereof is the dose indicated on the label of the drug and selected from any one of the doses for effective treatment indicated on the label of the drug.

[0103] In some embodiments, the emotional blunting occurs in connection with or as a result of the administration of a drug, and the methods for preventing or treating emotional blunting or its signs and symptoms described herein include the following steps: 1) Steps for discontinuing the drug; and 2) The step of administering a therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to a patient in need.

[0104] In some embodiments, the emotional blunting occurs in connection with or as a result of the administration of a drug, and the methods for preventing or treating emotional blunting or its signs and symptoms described herein include the following steps: 1) A step of maintaining the administration of the drug; and 2) The step of administering a therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to a patient in need.

[0105] In some embodiments, the emotional blunting occurs in connection with or as a result of the administration of a drug, and the methods for preventing or treating emotional blunting or its signs and symptoms described herein include the following steps: a. The step of discontinuing the drug for the treatment of CNS disease or disorder; and b. The step of administering a therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to a patient in need.

[0106] In some embodiments, the emotional blunting occurs in connection with or as a result of the administration of a drug, and the methods for preventing or treating emotional blunting or its signs and symptoms described herein include the following steps: a. The step of maintaining the administration of the drug for the treatment of CNS disease or disorder; and b. The step of administering a therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to a patient in need.

[0107] In some embodiments, methods for use in the prevention or treatment of emotional blunting, or 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, are for the prevention of emotional blunting in patients.

[0108] In some embodiments, a method for use in the prevention or treatment of emotional blunting, or 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, is for treating emotional blunting in a patient. In some embodiments, the emotional blunting is related to a disease or disorder of the CNS. In some embodiments, the emotional blunting is related to an underlying CNS disease or disorder.

[0109] In some embodiments, the emotional blunting is observed in connection with or as a result of the administration of a drug, which is intended to treat one or more CNS disorders or their signs and symptoms. In some embodiments, the emotional blunting is reported by the patient. In some embodiments, the emotional blunting is diagnosed by a practitioner or physician. In some embodiments, the emotional blunting is reported by the patient as being caused by an inadequate response to medical treatment for a CNS disorder or condition.

[0110] In some embodiments, the emotional blunting is diagnosed by a general practitioner or physician evaluating the patient, and the evaluation includes the following steps: a) The step of explaining to the patient: “The emotional effects can vary, but may include, for example, feeling emotionally ‘numb’ or ‘blunted’ in some way; a lack of positive or negative emotions; feeling disconnected from the world around you; or ‘not caring at all’ about things that you used to care about.” b) A step to ask the question, "Have you experienced such emotional impacts in the past six weeks?" c) a step of evaluating the response to question b) to determine whether symptoms or signs of emotional blunting are present in the patient; and optionally by, d) If the assessment in step c) indicates that the patient is experiencing emotional blunting, the practitioner or physician decides to apply any method or use for treating emotional blunting described herein.

[0111] In some embodiments, if the patient's answer to the question asked in step b) is "yes," then step c) of the practitioner's or physician's evaluation leads to the conclusion of the presence of emotional blunting.

[0112] In some embodiments, the emotional blunting is diagnosed by a general practitioner or physician evaluating the patient, and the evaluation includes the following steps: a) The step of explaining to the patient: “The emotional effects can vary, but may include, for example, feeling emotionally ‘numb’ or ‘blunted’ in some way; a lack of positive or negative emotions; feeling disconnected from the world around you; or ‘not caring at all’ about things that you used to care about.” b) A step to ask the question, "Have you experienced such emotional impacts in the past six weeks?" c) Evaluate the response to question b), and if the patient answers "yes" to question b), determine that symptoms or signs of emotional blunting are present in the patient (in some embodiments, steps a) to c) of the practitioner's or physician's evaluation may be supplemented or replaced by an evaluation using the ODQ total score or an equivalent evaluation, the ODQ total score of which is calculated based on the ODQ guidelines); and optionally, d) If the assessment in step c) indicates that the patient is experiencing emotional blunting, the practitioner or physician decides to apply any method or use for treating emotional blunting described herein.

[0113] The ODQ was developed to specifically assess the symptoms of emotional blunting in patients with MDD (Price et al., 2012 (above)). Results from this analysis of data from the COMPLETE study demonstrate that the ODQ ((copyright) Oxford University Innovation Limited, 2011) (both a portion of the questionnaire covering the first two sections and the complete questionnaire including all three sections) captures MDD situations and symptoms that are not adequately covered by other scales commonly used to assess the severity of depression.

[0114] A low correlation was observed between the ODQ score ((Copyright) Oxford University Innovation Limited, 2011) and the baseline MADRS total score, and also between the ODQ score and MADRS items that specifically assess the symptoms of anhedonia, namely "feelings" and "fatigue."

[0115] The highest correlation was observed between the ODQ score ((Copyright) Oxford University Innovation Limited, 2011) and the baseline MEI total score, showing some overlap with this motivational scale. While not bound by this theory, this may be due to the fact that patients with emotional blunting are likely to underreport symptoms of depression and disorder, given that they are detached and numb from most emotions and sensations (including emotional blunting itself). Improvements were seen in all different scales in response to therapy. A significant correlation was observed between the mean change in the ODQ score ((Copyright) Oxford University Innovation Limited, 2011) and other assessment scores after 8 weeks of vortioxetine treatment, suggesting that the ODQ is sensitive to changes in clinical status.

[0116] This has the advantage of being able to assess the full range of symptoms of emotional blunting from the patient's perspective, that is, the absence of both positive and negative emotions. For example, a patient might report: "All my emotions, both 'pleasant' and 'unpleasant,' are toned down," or "I can't fully enjoy things that should bring me joy, such as beautiful places or objects or music," or "Unpleasant emotions such as sadness, disappointment, and upset feel toned down or somehow different." Regarding the effects of emotional blunting, a patient might report that "everyday life doesn't affect me emotionally in the same way it did when I was previously ill or had problems."

[0117] definition As used herein, the term “vortioxetine” can be used interchangeably with the terms “1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]-piperazine” or “Lu AA21004,” which are known as the active ingredients of Brintellix® or Trintellix®. Accordingly, as used herein, the phrase “1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof” discloses all pharmaceutically acceptable salts of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]-piperazine, and the phrase “1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof” specifically includes “vortioxetine,” “1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]-piperazine HBr,” or “Lu AA21004.”

[0118] As used herein, the term “emotional blunting” is interchangeable with the term “emotional paralysis” and refers to an individual’s subjective experience of being unable to feel emotions, accompanied by a lack of care and concern for oneself and others. Similarly, the terms “paralysis” or “to paralyze” or other derivatives are interchangeable with the terms “blunting” or “blunted” and other derivatives. As used herein, “emotional paralysis” or “emotional blunting” is distinct from depression. In some embodiments, emotional blunting is a direct result of medical treatment for a CNS disorder or condition, such as antidepressants or antipsychotics. In some embodiments, emotional blunting is a direct result of medical treatment for a CNS disorder or condition, such as antidepressants. In some embodiments, emotional blunting is a direct result of medical treatment for a CNS disorder or condition, such as SSRIs or SNRIs. In some embodiments, emotional blunting as described herein may be an underlying symptom of a CNS disorder or condition. In some embodiments, the emotional blunting described herein may be a latent symptom of a CNS disorder or condition that is revealed by treatment with a drug for a related or unrelated CNS disorder or condition, such as an antidepressant or antipsychotic. The term “latent” in this context means that when an antidepressant alleviates depression, the latent symptom of emotional blunting may be revealed rather than triggered.

[0119] Therefore, emotional blunting, as used herein, means a lack of emotion (including depression and sadness). In contrast to a depressed person, a blunted or paralyzed person lacks respect, concern, care, or empathy for themselves or others. Common terms used by traumatized individuals to describe this paralyzed state of mind include detachment, paralysis, icy cold, emptiness, dead, and empty, devoid of any emotion, concern, or interest in anyone or anything. Families generally perceive paralyzed relatives as cold, heartless, and emotionally unresponsive. A severely paralyzed person may have a blank expression rather than a depressed one. Very rarely, an emotionally paralyzed person may appear angry or sad to others, but will be embarrassed or deny it when questioned about their own expressions of anger or sadness.

[0120] The term "CNS disorder or condition" can be used interchangeably with "CNS disorder or impairment" and refers to a broad range of conditions in which the brain does not perform its normal functions, limiting health and the ability to function. This condition may result from hereditary metabolic disorders; infections, degenerative conditions, strokes, brain tumors, or other damage; or from unknown or multiple factors. Movement disorders such as Parkinson's disease, dystonia, and essential tremor are CNS conditions. What they have in common is the loss of sufficient, intact neural circuits that regulate various functions, such as memory formation (in Alzheimer's disease) and voluntary movement (in movement disorders). While most conditions in this group cannot be completely cured, the symptoms of central nervous system disorders can often be managed through a variety of therapies, from medical interventions to surgical procedures. New therapies are also being researched. For example, physicians researching the potential of chemotherapy for brain tumors or gene therapy for Parkinson's disease are interested in brain and cerebrospinal infusion therapies that deliver anticancer drugs or replacement genes to brain regions whose activity may help manage or limit the effects of the disease. The terms “CNS disease or condition” or “CNS disorder” mean including mental disorders such as schizophrenia, schizoaffective disorder, schizophrenia-like disorder, catatonia, and delusional disorder; mood disorders such as bipolar disorder, cyclothymic disorder, major depression, dysthymia, and premenstrual dysphoric disorder; and substance use disorders.

[0121] As used herein, the term “CNS disease or condition” may be used interchangeably with the term “CNS disease or disorder” and includes psychiatric and neurological disorders. In some embodiments, “CNS disease or condition” includes psychiatric and neurological disorders such as depression, e.g., MDD or MDE, PTSD, schizophrenia, Parkinson’s disease, autism, vascular dementia, and multiple system atrophy. In some embodiments, CNS disease or condition includes one or more of MDD or MDE, PTSD, schizophrenia, Parkinson’s disease, autism, vascular dementia, and multiple system atrophy.

[0122] Psychosis is a part of schizophrenia and can also be part of other disorders. Psychosis is a concept that describes specific symptoms. Schizophrenia is a mental disorder that has psychotic features. Symptoms of psychosis include, but do not necessarily have to be, hallucinations, delusions, confusion, inability to think clearly, rapid and / or dizzy thinking, confused speech, disorganized behavior, and catatonic behavior. In schizophrenia, psychosis is the first criterion that must be met for a diagnosis of schizophrenia. Schizophrenia does not exist without psychosis, but psychosis can occur independently without schizophrenia. Other disorders that may be associated with "psychosis" may be other mental disorders (schizophrenia, schizoaffective disorder, schizophrenia-like disorder, catatonia, delusional disorder), mood disorders (bipolar disorder, cyclothymic disorder, major depressive disorder, dysthymia, premenstrual dysphoric disorder), and substance use disorders.

[0123] Patients with schizophrenia experience, for example, psychosis, negative symptoms, and a reduced level of functioning in daily life. "Affective blunting" may coexist with or be part of negative symptoms associated with schizophrenia (also known as schizoaffective disorder) or symptoms seen in non-schizophrenic patients with other CNS disorders or disorders, and may be closely related to "negative symptoms." "Negative symptoms" may also include apathy, aphasia, lethargy, anhedonia, unsociability, emotional withdrawal, and social withdrawal. Patients with schizophrenia are sometimes prescribed antidepressants or mood stabilizers to manage mood symptoms.

[0124] Accordingly, the terms “antipsychotic drugs” or “antipsychotic agents” or “nerve relaxants” as used herein may be used interchangeably and may be included in the terms “medications for the treatment of schizophrenia” or “medical treatment for schizophrenia” or similar phrases as used herein, since patients with schizophrenia often receive treatment for their psychosis with such drugs.

[0125] Accordingly, the terms “medicines for the treatment of schizophrenia” or “medical treatment for schizophrenia,” or similar terms used herein, may include “atypical antipsychotics” and / or “typical antipsychotics.”

[0126] In the present invention, the “atypical antipsychotic” may be selected from the group including, for example, aripiprazole, iloperidone, ziprasidone, lurasidone, risperidone, brexpriprazole, asenapine, quetiapine, caliprazine, and olanzapine. Clozapine is a special atypical antipsychotic and is usually prescribed only when other antipsychotics fail to alleviate symptoms or when a schizophrenic patient is suffering from suicidal ideation.

[0127] In the present invention, the "typical antipsychotic drug" may be selected from the group including, for example, haloperidol, roxapine, thiothixen, fluphenazine, chlorpromazine, perphenazine, and trifluoperazine.

[0128] There are other methods of classifying antipsychotic drugs based on their chemical structure. According to the World Health Organization's ("WHO") ATC / DDD index, antipsychotic drugs are classified into class N05A and are further subdivided mainly based on their chemical structure; subclass A consists of phenothiazines with aliphatic side chains, including N05AA01 chlorpromazine, N05AA02 levomepromazine, N05AA03 promazine, N05AA04 acepromazine, N05AA05 triflupromazine, N05AA06 siamemazine, and N05AA07 chlorproetazine; subclass B consists of N05AB01 diki These are phenothiazines having a piperazine structure, comprising silazine, N05AB02 fluphenazine, N05AB03 perphenazine, N05AB04 prochlorperazine, N05AB05 thiopropazate, N05AB06 trifluoperazine, N05AB07 acetophenazine, N05AB08 thioproperazine, N05AB09 butaperazine, and N05AB10 perazine; subclass C is N05AC01 pericyazine, N05AC02 thioridazine, N05AC03 mesolidazine, and N05AC04 pipethia These are phenothiazines containing din and having a piperidine structure; subclass D includes butyrophenone derivatives, including N05AD01 haloperidol, N05AD02 trifluperidol, N05AD03 merperone, N05AD04 moperone, N05AD0 pipemperone, N05AD06 bromperidol, N05AD07 bemperidol, N05AD08 droperidol, and N05AD09 fluanisone; subclass E includes N05AE01 oxypertine, N05AE02 morindone, and N05AE03 certine Subclass F is an indole derivative comprising dole, N05AE04 ziprasidone, and N05AE05 lurasidone; subclass G is a diphenylbutylpiperidine derivative comprising N05AG01 flupentixol, N05AF02 clopentixol, N05AF03 chlorprothixene, N05AF04 thiothixene, and N05AF05 zuclopentixol; subclass G is a diphenylbutylpiperidine derivative comprising N05AG01 fluspirylene, N05AG02 pimozide, and N05AG03 penfluridol;Subclass H comprises diazepines, oxazepines, thiazepines, and oxepins, including N05AH01 roxapine, N05AH02 clozapine, N05AH03 olanzapine, N05AH04 quetiapine, N05AH05 asenapine, and N05AH06 clotiapine; subclass L comprises benzamides, including N05AL01 sulpiride, N05AL02 sultopride, N05AL03 tiapride, N05AL04 remoxypride, N05AL05 amisulpride, N05AL06 veralipride, and N05AL07 levosulpiride; and subclass N comprises lithium, including N05AN01 lithium.

[0129] According to the WHO ATC / DDD index, other antipsychotics were classified as Class N05AX, which included protipendyl (code N05AX07), risperidone (N05AX08), mosapramine (N05AX10), zotepine (N05AX11), aripiprazole (N05AX12), paliperidone (N05AX13), iloperioden (N05AX14), ccariprazine (N05AX15), brexpriprazole (N05AX16), and pimavanserin (N05AX17).

[0130] In some embodiments, “emotional blunting” is observed in patients with signs and / or symptoms of one or more CNS disorders or conditions, patients diagnosed with one or more CNS disorders, and / or patients receiving medical treatment for one or more CNS disorders or conditions.

[0131] In some manifestations, when blunting is severe, patients may be unable to feel any emotions and may exhibit a blank, lifeless appearance. In some manifestations, individuals with blunted emotions are generally unresponsive to their environment and socially withdrawn. This unresponsiveness to the environment may be a complex disorder representing a reduced level of arousal and consciousness and a loss of interest in the outside world. Individuals with blunted emotions may not feel empathy or connection with others. In social situations, they tend to feel alienated and disconnected. In some manifestations, emotional blunting is associated with bodily paralysis and / or paresthesia, as well as a feeling of heaviness or apathy. In some manifestations, severe emotional blunting may be accompanied by severe impairment of concentration and memory, including memory loss of events that occurred during the paralyzed state. In some manifestations, all types of information processing may be significantly impaired. When emotional blunting is severe and prolonged, it is usually accompanied by a lack of motivation, interest, or pleasure in life activities. Therefore, in some cases, a person who has become desensitized may suffer emotional, mental, psychological, and social impairments.

[0132] Emotional numbness is generally assessed as a subjective symptom. In some manifestations, emotional numbness or blunting can vary in three parameters: duration, severity, and social context. In some manifestations, such numbness or blunting can be experienced continuously or intermittently for minutes, hours, days, months, or years. In some manifestations, individuals with severe or profound emotional numbness or blunting may feel no emotion at all. In some manifestations, with less severe numbness or blunting, emotions associated with high levels of physiological arousal may be experienced, such as anger, fear, and vulnerability. In some manifestations, tender, affectionate feelings may not be felt. Some individuals with severely blunted emotions may be able to feel affection and concern for a specific individual(s) for a period of time. This could be a child, a trusted spouse, or a companion who survived a traumatic event.

[0133] In some embodiments, emotional numbness may be accompanied by physical experiences such as heaviness or numbness of the body, tingling or numbness, tingling or paralysis of a part of the body, derelictness, alienation, and separation from others. In some embodiments, cognitive impairment may include confusion, memory loss, difficulty concentrating, indecisiveness, inability to plan future actions, and paralysis of will. In some embodiments, cognitive impairment may occur independently of levels of physiological arousal or distress; forgetfulness, disorientation, or confusion may occur without a preceding apparent increase in stress or anxiety.

[0134] In some aspects, patients may be unable to distinguish between the mental states of paralysis and depression. In some aspects, cognitive impairments, including a lack of self-awareness, may impair an individual's ability to distinguish between paralysis and depression. In some aspects, individuals may frequently transition between depressive states and paralyzed or blunt states, making it difficult to distinguish subjective experiences. In some aspects, paralysis and depression also share certain symptoms, including impaired concentration and memory, and a lack of interest in or pleasure from life activities.

[0135] In some cases, a mental state of emotional numbness or blunting is a condition that impairs the daily life of the patient and their family. In some cases, numbness or blunting interferes with an individual's ability to enjoy or participate in life's activities (work, relationships, sex, etc.) and their ability to feel genuine affection, interest, or concern for someone or something, which often leads to discord in marriages and families.

[0136] In some cases, individuals experiencing emotional numbness may seek out exciting and risky activities such as skydiving, racing cars, gambling, drug abuse, and self-injury in an attempt to escape the deadly effects of the numbness. In some cases, these activities may be predicated on an uncontrollable, addictive urge accompanied by an intense craving.

[0137] In some embodiments, the presence of emotional numbness or blunting can be clinically assessed, for example, using the tests and evaluation methods described herein.

[0138] In one embodiment, a neuropsychological test for assessing cognitive function may be a digital symbol substitution test ("DSST").

[0139] In some aspects, the presence of emotional blunting can be clinically assessed as part of the psychiatric diagnosis of PTSD.

[0140] In some aspects, signs and / or symptoms of emotional blunting reported by patients can be gathered from, at a minimum, the patient's response to the question, “Have you experienced such emotional effects in the past six weeks?”

[0141] In some embodiments, signs and / or symptoms of emotional blunting reported by a patient can be gathered from the patient's response to the question, “Have you experienced such emotional effects in the past six weeks?” and the patient is informed about the general emotional effects of emotional blunting.

[0142] In some aspects, signs and / or symptoms of emotional blunting reported by a patient can be gathered from at least the patient's response to the question, “Have you experienced such emotional effects in the last six weeks?”, and the patient is informed about the general emotional effects of emotional blunting, which can be described as: “The emotional effects vary, but may include, for example, feeling emotionally ‘numb’ or ‘blunt’ in some way; a lack of positive or negative emotions; feeling disconnected from the world around you; or ‘not caring at all’ about things that used to care about.”

[0143] As used herein, the terms “Oxford Depression Questionnaire (ODQ)” or “ODQ” refer to the Oxford Depression Questionnaire ("ODQ"). The ODQ is a patient-centered self-report measure of emotional symptoms present in patients treated with antidepressants, and was formerly known as the Oxford Questionnaire on Emotional Side-Effects of Antidepressants ("OQuESA" or "OQESA"). (Jonathan Price et al. “The Oxford Quastionaire on Emotional Side-Effects on Atidepressants (OQuESA): Development, validity, reliability and sensetivity change” Journal of Affective Discorders, 140(2012), 66-74; Goodwin GM, Price J, Bodinat CD, Laredo J. Emotional blunting with antidepressant treatments: A survey among depressed patients. J Affect Discord. 2017;221:31-35 (these are incorporated herein by reference in their entirety)).

[0144] The ODQ used and referenced in this invention is the Oxford Depression Questionnaire (ODQ) ((Copyright) Oxford University Innovation Limited, 2011), which requires authorization from Oxford University Innovation Limited. The ODQ is a 26-item patient self-administered questionnaire spanning three sections and covering four aspects (derived from qualitative research): indifference ("NC"), emotional detachment ("ED"), decreased positivity ("PR"), and general decline ("GR"). An additional aspect, antidepressant as causative ("AC"), may also be scored as needed. The ODQ referred to herein includes three sections. Section 1 assesses the experience of emotional blunting over the past week: 12 items, three from each of the four aspects (NC, ED, PR, and GR). The recall period is the last week. Section 2 compares the participant's experience of emotional blunting over the past week to their experience of emotional blunting before developing depression: eight items, two from each of the four aspects, compare the participant's experience from the previous week to their experience before developing the illness / problem. Section 3 (6 items) assesses the patient's perception of the relationship between their current antidepressant and emotional blunting, and whether this effect has affected treatment adherence. Section 3 describes aspect AC. Section 3 is to be completed only by respondents who are currently prescribed antidepressants. This section addresses the extent to which participants believe their emotional problems are caused by their antidepressants and the extent to which they consider them “emotional side effects.” It also addresses the potential impact of emotional side effects on antidepressant adherence. The response options are based on a 5-point Likert scale. Therefore, each item is evaluated on a 5-point Likert scale from 1 (disagree) to 5 (agree); a higher score (4 or 5 for each item) indicates greater emotional blunting, i.e., a higher ODQ value reflects a higher level of emotional blunting. The results can be presented on an aspect basis or summed up to obtain an overall ODQ score.ODQ scores excluding AC domain aspects (ODQ-20) range from 20 to 100, while ODQ scores including AC domain aspects (ODQ-26) range from 26 to 130. In the COMPLETE study, patients completed ODQ-26.

[0145] Therefore, the ODQ scores referred to in this application are in accordance with the Oxford Depression Questionnaire (ODQ) (Copyright: Oxford University Innovation Limited, 2011).

[0146] The ODQ consists of the following questions: Section 1: All of your emotions, both "pleasant" and "unpleasant," are "toned down"; you don't enjoy things that should bring you joy, such as beautiful places or objects or music; you're not as considerate of other people's feelings as you should be; you have problems at home because you're not very interested in things; unpleasant emotions like sadness, disappointment and upset feel toned down or somehow different; you don't look forward to things with eager anticipation; you're not very sympathetic to people; you feel "out of it" and detached from the world around you; your emotions lack strength; you don't have the passion and enthusiasm for life that you should; other people's upsets don't affect you; you have problems at work or college because you're not very interested in things. Section 2: Daily life does not affect me as emotionally as it did before the illness or problem occurred; I do not experience as much joy as before the illness / problem occurred; I do not react as much to the emotions of others (sadness, anger, upset, etc.) as before the illness / problem occurred; I do not worry as much about daily responsibilities as before the illness / problem occurred; my emotions are numb / dulled / flatter than before the illness / problem occurred; I do not feel as "good" about the good things in life as before the illness / problem occurred; I do not sympathize with others as much as before the illness / problem occurred; I do not care as much about things as before the illness / problem occurred. Section 3: Antidepressants interfere with feeling my emotions in some way; Antidepressants seem to make me stop caring about things that are important to me; Antidepressants seem to make me feel emotionally disconnected from the people around me; Antidepressants prevent me from feeling happy emotions; Antidepressants alter how I feel my emotions in a way that is not helpful / useful at the moment; I am considering (or have already stopped) discontinuing antidepressants due to emotional side effects.

[0147] Future ODQs may be replaced by subsequent versions of the ODQ to determine whether a patient is experiencing emotional blunting. Therefore, the terms “or equivalent” as used herein in relation to the ODQ scale mean that the ODQ may be replaced by subsequent versions of the questionnaire. Accordingly, the scales and scoring systems must be adapted to the updated scales and the guidelines for the ODQ scale provided in the new version. Accordingly, the term “ODQ guidelines” or similar phrases as used herein mean the guidance provided with the ODQ license, which guides users of the ODQ on which questions to ask and how to score them, including cutoff values ​​for when emotional blunting is present and when it is not.

[0148] In one embodiment, patient-reported signs and / or symptoms of emotional blunting may be collected using one or more of the following standardized questionnaires: ODQ, MEI, or SDS.

[0149] In one embodiment, patient-reported signs and / or symptoms of emotional blunting can be collected at least by the ODQ.

[0150] In some embodiments, emotional blunting is assessed using the guidelines outlined in the definitions of numbness and avoidance in the Diagnostic and Statistical Manual of the American Psychiatric Association.

[0151] In one embodiment, patient-reported signs and / or symptoms of emotional blunting may be collected by one or more of the following scales that can be used to assess a patient's signs and / or symptoms of emotional blunting: the Assessment of Negative Symptoms ("SANS"), the Clinical Assessment Interview for Negative Symptoms ("CAINS"), and the Brief Negative Symptom Scale ("BNSS").

[0152] In one embodiment, patient-reported signs and / or symptoms of emotional blunting may be collected using one or more of the following standardized questionnaires: the ODQ, the Positive and Negative Schizophrenia Symptoms Scale ("PANSS") (Peralta V, & Cuesta MJ. Psychometric properties of the positive and negative syndrome scale (PANSS) in schizophrenia. Psychiatry Research. 1994;53:31-40; Lancu I, Poreh A, Lehman B, Shamir E, & Kotler M. The positive and negative symptom questionnaire: a self-report scale in schizophrenia. Comprehensive Psychiatry. 2005;46:61-66 (each incorporated herein in its entirety by reference)), including “blunted effect” and “emotional withdrawal” and a rating scale for emotional blunting("RSEB")(Kilian, S., Asmal, L., Goosen, A., Chiliza, B., Phahladira, L., & Emsley, R.(2015). Instruments measuring blunted effect in schizophrenia: A systematic review. PLoS One, 10(6) (the entire article is incorporated herein by reference)).

[0153] In some embodiments, the presence of emotional blunting can be clinically assessed, for example, using the tests and assessment methods described herein. In one embodiment, patient-reported signs, symptoms, and / or functional outcomes of emotional blunting can be collected by one or more of the following standardized questionnaires: ODQ, MEI, and SDS. In one embodiment, patient-reported signs and / or symptoms of emotional blunting can be collected by ODQ.

[0154] In some embodiments, the presence of emotional blunting can be clinically assessed, for example, using the tests and assessment methods described herein. In one embodiment, patient-reported signs, symptoms, and / or functional outcomes of emotional blunting may include the collection of information using one or more of the following standardized questionnaires: ODQ, MEI, and SDS. In one embodiment, patient-reported signs and / or symptoms of emotional blunting can be collected by ODQ.

[0155] In some embodiments, the presence of emotional blunting can be clinically assessed, for example, using the tests and assessment methods described herein. In one embodiment, patient-reported signs and / or symptoms of emotional blunting may include the collection of information using one or more of the following standardized questionnaires: ODQ or MEI. In one embodiment, patient-reported signs and / or symptoms of emotional blunting can be collected by ODQ.

[0156] In one embodiment, clinician assessment of signs and symptoms of emotional blunting may include gathering information using one or more of the following standardized methods: the Montgomery-Asberg Depression Rating Scale ("MADRS"), the Clinical Global Impression-Severity of Illness ("CGI-S"), and the Clinical Global Impression-Global Improvement ("CGI-I").

[0157] In one embodiment, clinician assessment of signs and symptoms of emotional blunting may include the collection of information by one or more of the following standardized methods: CGI-S and CGI-I.

[0158] In some embodiments, the presence of emotional blunting can be clinically assessed, for example, using the tests and assessment methods described herein. In one embodiment, patient-reported signs and / or symptoms of emotional blunting can be collected by one or more of the following standardized questionnaires: ODQ and MEI. In one embodiment, patient-reported signs and / or symptoms of emotional blunting can be collected by ODQ.

[0159] In one embodiment, clinician assessment of signs and symptoms of emotional blunting can be collected by one or more of the following standardized methods: MADRS, CGI-S, and CGI-I.

[0160] In one embodiment, clinician assessment of signs and symptoms of emotional blunting can be collected by one or more of the following standardized methods: CGI-S and CGI-I.

[0161] Numbness (and avoidance) is one of the four categories of mental disorders that an individual must meet to be diagnosed with PTSD. The American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (CRSD) defines numbness (and avoidance) as having seven items, and any three of these items must be present for the category (numbness and avoidance) to be met. Affective numbness is specifically represented by two of the seven items. One item represents a limited range of emotions, such as an inability to feel affection. The second item represents a markedly reduced interest in important activities. Paralysis is defined in this manual as “persistent avoidance of trauma-related stimuli or paralysis of general responses (that were not present prior to the trauma)” as indicated by at least the following three: (1) efforts to avoid thoughts or feelings related to the trauma; (2) efforts to avoid activities or situations that recall the trauma; (3) inability to recall significant circumstances of the trauma (psychogenic amnesia); (4) markedly diminished interest in significant activities (in young children, loss of recently acquired developmental skills such as toilet training or language skills); (5) feelings of isolation or alienation from others; (6) limited range of emotions, e.g., inability to feel affection; and (7) a sense of a shortened future, e.g., no expectations of a career, marriage, children, or longevity.

[0162] In one embodiment, adverse events including signs and symptoms of emotional blunting may be recorded or reported using safety assessments that are commonly used in the reporting or diagnosis of adverse events ("AEs").

[0163] In one embodiment, discontinuation of a patient's treatment due to an adverse event related to emotional blunting may be recorded or reported according to the general method of the Discontinuation-Emergent Signs and Symptoms Scale ("DESS").

[0164] In one embodiment, the symptoms and signs of emotional blunting can be recorded by voice recording, and patient data obtained through a mobile phone application such as Discovery by Mindstrong can be passively collected.

[0165] As used herein, the terms “treatment” and “to treat” mean the management and care of a patient for the purpose of combating a condition such as a disease or disorder. This term is intended to encompass the full range of treatments for a given condition in which a patient is suffering, including the administration of active compounds to alleviate symptoms or complications, to slow the progression of a disease, disorder, or condition, to alleviate or reduce symptoms or complications, and / or to cure or eliminate a disease, disorder, or condition, and to prevent the condition. Prevention should be understood as the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of active compounds to prevent the onset of symptoms or complications. In addition, “to treat” or “treatment” includes, though not required, protocols that may result in complete relief of signs and / or symptoms, do not require a cure, and may have only a slight effect on the patient.

[0166] As used herein, the terms “reduction” or “reduce” include, for example, a decrease, mitigation, or reduction of the symptoms or signs of emotional blunting, without requiring the complete elimination of the signs and / or symptoms of emotional blunting, and without requiring a cure.

[0167] As used herein, the terms “prevents” or “preventing” are interchangeable with the term “preventive,” and can partially or completely avoid the signs and / or symptoms of a disease or condition in accordance with specific instructions, treatment regimens, or drug administrations. Accordingly, methods used in aspects and embodiments of the present invention can prevent the onset of signs and symptoms of emotional blunting as a result of treatment of a patient with an antidepressant, or as a result of an underlying CNS disorder or disorder, such as depression or PTSD.

[0168] Nevertheless, in some embodiments, prophylactic and therapeutic treatments are two distinct aspects of the present invention. The patient to be treated is preferably a mammal, particularly a human.

[0169] As used herein, the term “signs” refers to signs observed by a healthcare professional, such as a physician / internist, when referring to a disease, disorder, or condition. Therefore, “signs” include physical symptoms and other objective measures. As used herein, the term “symptoms” when referring to a disease, disorder, or condition refers to what a patient experiences or reports, and is often subjective. Therefore, the ODQ is a patient-centered, self-report scale of affective symptoms present in patients treated with antidepressants. The ODQ can be used as a clinical tool to facilitate the identification of patients with affective blunting syndrome. The ODQ can also be used in research studies to deepen our understanding of the nature, causes, and especially treatment of this phenomenon. The Digital Symbol Substitution Test ("DSST") was initiated more than a century ago as an experimental tool to understand human associative learning. Its clinical usefulness was first recognized in the 1940s due to its brevity and high discriminant validity, and today the DSST is one of the most commonly used tests in clinical neuropsychology. The DSST is a paper-and-pencil cognitive test presented on a single sheet of paper, requiring the subject to match symbols and numbers according to a key at the top of the page. The subject copies the symbols into the space below the row of numbers. The DSST is perhaps the most commonly used test in all neuropsychology due to several inherent characteristics: conciseness, reliability, and minimal influence of language, culture, and education on test performance. The DSST provides a practical and effective method for monitoring cognitive function over time in clinical practice. The MEI is a 27-item scale designed to assess fatigue and lethargy. This scale was initially developed to evaluate interventions aimed at improving motivation and energy in patients with depression, but further evaluation can extend its clinical application to other patient groups (Fehnel, SE, Bann, CM, Hogue, SL, Kwong, WJ, Mahajan, SS (2004) The development and psychometric evaluation of the motivation and energy inventory. Qual.Life.Res.13, 1321-1336 (the entire article is incorporated herein by reference)).MEI assesses three factors: mental or cognitive energy, social motivation, and physical energy. SDS was developed to assess impairment in three interrelated domains: work / school, social life, and home life. SDS is well-known and used by researchers and clinicians. SDS is a patented self-report tool in which patients assess the degree to which their symptoms impair the aforementioned domains—responsibilities—using a 10-point visual analog scale that simultaneously evaluates the level of impairment using spatial visual, numerical, and verbal descriptive anchors.

[0170] In the context describing the present invention, the terms “a,” “an,” “the,” and similar references should be interpreted as encompassing both singular and plural forms unless otherwise indicated herein or unless the context clearly contradicts this interpretation. For example, the term “compound” should be understood, unless otherwise indicated, to refer to the various compounds of the present invention or specific described embodiments.

[0171] Unless otherwise indicated, all exact values ​​described herein represent the corresponding approximations. In some embodiments, all exact exemplary values ​​provided for a particular factor or measurement can be considered to also provide the corresponding approximate measurement, modified as necessary by "about".

[0172] Any aspect of the description herein of an aspect of the Invention that uses terms such as “comprising,” “having,” “including,” or “containing” with respect to one or more elements is intended, unless otherwise stated or unless clearly inconsistent with the context, to provide support for similar aspects or aspects of the Invention that “consist of,” “essentially consist of,” or “substantially contain” that particular element (unless otherwise stated or unless clearly inconsistent with the context, for example, a composition described herein as containing a particular element should be understood to also describe a composition consisting of that element).

[0173] As used herein, the term “appropriate dose” means a dose that is expected to produce a therapeutic effect and which may be discontinued and / or replaced with another drug in the event of no response, partial response, or insufficient response.

[0174] The “appropriate dose” of a drug for treating one or more CNS diseases or disorders shall be selected based on the evidence-based dose disclosed on the label of the drug.

[0175] As used herein, the term “insufficient response” means no response to drug treatment, a partial response to drug treatment, or a response to a drug that reveals signs and symptoms of emotional blunting.

[0176] As used herein, the term “develops” when referring to signs and / or symptoms of emotional blunting means a change from a state of absence of signs and / or symptoms of emotional blunting to one or more signs and / or symptoms of emotional blunting. Such one or more signs and / or symptoms may be assessed as described herein. A non-limiting example of one or more signs and / or symptoms of emotional blunting may be a “yes” response to screening question b) described herein, associated with an assessment made by a practicing physician or physician, or an assessment score equal to an ODQ total score greater than 30. A state of absence of such signs and / or symptoms may be assessed as described herein. A non-limiting example of a state of absence of signs and / or symptoms of emotional blunting may be a “no” response to screening question b) described herein, associated with an assessment made by a practicing physician or physician, or an assessment score equal to an ODQ total score of 26 or less.

[0177] As used herein, the term “worsening of” refers to a change from one or more signs and / or symptoms of emotional blunting to a more severe stage of signs and / or symptoms of emotional blunting (such as a change in the ODQ total score from over approximately 30 to approximately 60, from approximately 40 to approximately 55, or to approximately 50).

[0178] The phrase "the drug has an enhancing effect on serotonin transmission," or similar phrases referring to one or more drugs, is used to describe drugs such as antidepressants. Such drugs can affect serotonin transmission, for example, by increasing serotonin levels at certain levels. That is, some may affect serotonin reuptake, while others may inhibit serotonin release.

[0179] The phrase "the said drugs reduce the effect on dopaminergic transmission," or similar phrases referring to one or more drugs, is used to describe drugs such as antipsychotics and drugs used to treat schizophrenia. Such drugs may affect dopaminergic transmission, for example, by lowering the levels of dopamine at certain levels.

[0180] As used herein, the term “rapid onset” includes, when referring to the treatment described herein, a reduction in signs and symptoms such as ODQ or MEI scores, or a change from a “yes” answer to cleaning question b) described herein in relation to the assessment performed to a “no” answer within the first four weeks of treatment, preferably within two weeks or one week of treatment. Approximately 50% of patients may experience the effects of the treatment described herein within one week of taking 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof at doses of approximately 5 mg, approximately 10 mg, or approximately 20 mg per day, preferably approximately 10 mg or 20 mg per day.

[0181] Embodiment The following embodiments further elaborate on the invention outlined in the above embodiments. It should be recognized that one or more features of any embodiments disclosed herein can be combined and / or rearranged within the scope of the invention to provide further embodiments that are also within the scope of the invention.

[0182] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting in patients such as those suffering from CNS diseases or disorders.

[0183] In some embodiments of the present invention, the CNS disorder or disorder is selected from the group consisting of mental disorders such as psychosis, schizophrenia, schizoaffective disorder, schizophrenia-like disorder, catatonia, and delusional disorder; mood disorders such as bipolar disorder, cyclothymic disorder, major depressive disorder, dysthymia, and premenstrual dysphoric disorder; and substance use disorders.

[0184] In some embodiments, the present invention relates to a method for preventing or treating emotional blunting or its signs and symptoms in a patient, the method comprising administering a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to a patient in need thereof, preferably the administration of vortioxetine.

[0185] In some embodiments, the present invention relates to a method for preventing or treating emotional blunting or its signs and symptoms in a patient experiencing signs and symptoms of emotional blunting, the method comprising administering to a patient in need a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments, the present invention relates to a method for preventing or treating emotional blunting or its signs and symptoms in a patient, wherein the patient has experienced signs and symptoms of emotional blunting or has a medical history of signs and symptoms of emotional blunting resulting from the administration of a drug, and the drug causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, and the method comprises administering a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0187] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting in a patient, wherein the patient has experienced emotional blunting as part of a CNS disease or disorder, or has a medical history of signs and symptoms of emotional blunting resulting from the administration of a drug, and the drug causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0188] In some embodiments, the present invention relates to a method for preventing or treating emotional blunting or its signs and symptoms in a patient experiencing emotional blunting, wherein the patient has a medical history of signs and symptoms of emotional blunting in relation to the administration of a drug, and the drug causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, and the method comprises administering a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0189] In some embodiments, the present invention relates to a method for preventing or treating emotional blunting in a patient, wherein the patient has experienced emotional blunting or has a history of signs and symptoms of emotional blunting resulting from the administration of a drug, and the drug causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, and the method comprises administering a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to a patient in need.

[0190] In some embodiments, the present invention relates to a method for preventing or treating emotional blunting in a patient, wherein the patient has experienced emotional blunting or has a history of signs and symptoms of emotional blunting resulting from the administration of a drug in an appropriate dose, and the drug causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, and the method comprises administering a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to a patient in need.

[0191] In some embodiments, the present invention relates to a method for preventing or treating emotional blunting in a patient, wherein the patient has experienced emotional blunting or has a history of signs and symptoms of emotional blunting resulting from an inadequate response to medical treatment, and the agent causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, and the method comprises administering a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0192] In some embodiments, the present invention relates to a method for preventing or treating emotional blunting in a patient, wherein the patient has experienced emotional blunting or has a history of signs and symptoms of emotional blunting resulting from an inadequate response to medical treatment for a CNS disorder or condition, and the agent causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, and the method comprises administering a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0193] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting as seen in any one of the prior embodiments relating to the administration of an appropriate dose of an agent for the treatment of one or more CNS disorders or disorders, wherein the one or more CNS disorders or disorders are selected from the group of mental disorders such as schizophrenia, schizoaffective disorder, schizophrenia-like disorder, catatonia, and delusional disorder; mood disorders such as bipolar disorder, cyclothymic disorder, major depression, dysthymia, and premenstrual dysphoric disorder; and substance use disorders, wherein the agent is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, and the appropriate dose of the agent is the dose indicated on the label of the agent.

[0194] In some embodiments, the drugs or medical treatments for CNS disorders or disorders may cause emotional blunting due to an insufficient response to the drugs or medical treatments, and the drugs or medical treatments have an enhancing effect on serotonergic transmission.

[0195] In some embodiments, the drugs or medical treatments for CNS disorders or disorders may cause emotional blunting due to an insufficient response to the drugs or medical treatments, and the drugs or medical treatments have an enhancing effect on serotonergic transmission without affecting other neurotransmitters.

[0196] In some embodiments, the drug or medical treatment for a CNS disorder or disorder may cause emotional blunting due to an inadequate response to the drug or medical treatment, and the drug or medical treatment is selected from the SSRI or SNRI class.

[0197] In some embodiments, the drug or medical treatment for CNS disease or disorder may cause emotional blunting due to an inadequate response to the drug or medical treatment, and the drug or medical treatment is an SSRI.

[0198] In some embodiments, the drug or medical treatment for CNS disease or disorder may cause emotional blunting due to an inadequate response to the drug or medical treatment, and the drug or medical treatment is an SSRI selected from the group consisting of escitalopram, paroxetine, sertraline, and citalopram.

[0199] In some embodiments, the drug or medical treatment for CNS disease or disorder may cause emotional blunting due to an inadequate response to the drug or medical treatment, and the drug or medical treatment is an SNRI selected from the group consisting of venlafaxine and duloxetine.

[0200] In some embodiments, the drugs or medical treatments for CNS disorders or disorders may result in emotional blunting due to an inadequate response to the drugs or medical treatments, and the drugs or medical treatments are selected from drugs that reduce dopaminergic transmission.

[0201] In some embodiments, the drugs or medical treatments for CNS disorders or disorders may result in emotional blunting due to an inadequate response to the drugs or medical treatments, and the drugs or medical treatments are selected from drugs used to treat schizophrenia.

[0202] In some embodiments, the drugs or medical treatments for CNS disorders or disorders may result in emotional blunting due to an inadequate response to the drugs or medical treatments, and the drugs or medical treatments may be selected from drugs used to treat schizophrenia, and such drugs may be selected from the group of mental disorders such as psychosis, schizophrenia, schizoaffective disorder, schizophrenia-like disorder, catatonia, and delusional disorder; mood disorders such as bipolar disorder, cyclothymic disorder, major depression, dysthymia, and premenstrual dysphoric disorder; and substance use disorders.

[0203] In some embodiments, the drug or medical treatment for CNS disease or disorder may cause emotional blunting due to an inadequate response to the drug or medical treatment, and the drug or medical treatment is selected from ATC / DDD WHO Class N05A.

[0204] In some embodiments, the drug or medical treatment for CNS disorders or disorders may result in emotional blunting due to an inadequate response to the drug or medical treatment, and the drug or medical treatment is selected from a class of typical or atypical antipsychotics.

[0205] In some embodiments, if a patient is experiencing signs and symptoms of emotional blunting, they are treated with the administration of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof according to the present invention, including prophylactic measures. The table below shows the patient types in the middle column that may be experiencing emotional blunting and for which treatment according to the present invention may be beneficial. The right column shows a recommended treatment plan.

[0206] [Table 4]

[0207] [Table 5]

[0208] [Table 6]

[0209] In some embodiments, the patient is treated according to the present invention, and the patient and treatment are selected from any one of the examples A, A1-A4, and B-O shown in the table above.

[0210] In some cases, patients are selected and treated according to any one of the criteria in the table above.

[0211] In some embodiments, the patient is selected and treated according to scenario A in the table above. In some embodiments, the patient is selected and treated according to scenario A1 in the table above. In some embodiments, the patient is selected and treated according to scenario A2 in the table above. In some embodiments, the patient is selected and treated according to scenario A3 in the table above. In some embodiments, the patient is selected and treated according to scenario A4 in the table above. In some embodiments, the patient is selected and treated according to scenario B in the table above. In some embodiments, the patient is selected and treated according to scenario C in the table above. In some embodiments, the patient is selected and treated according to scenario D in the table above. In some embodiments, the patient is selected and treated according to scenario E in the table above. In some embodiments, the patient is selected and treated according to scenario F in the table above. In some embodiments, the patient is selected and treated according to scenario G in the table above. In some embodiments, the patient is selected and treated according to scenario H in the table above. In some embodiments, the patient is selected and treated according to scenario I in the table above. In some embodiments, the patient is selected and treated according to scenario J in the table above. In some embodiments, the patient is selected and treated according to scenario K in the table above. In some embodiments, the patient is selected and treated according to scenario L in the table above. In some embodiments, the patient is selected and treated according to scenario M in the table above. In some embodiments, the patient is selected and treated according to scenario N in the table above. In some embodiments, the patient is selected and treated according to scenario O in the table above.

[0212] In some aspects of the present invention, if a practicing physician or doctor confirms, through evaluation of the patient, that signs and symptoms of emotional blunting are present in the patient, they may decide to apply the methods or uses for treating emotional blunting described herein.

[0213] In some aspects of the present invention, if a practicing physician or doctor determines, through patient assessment, that the patient has experienced emotional blunting, they may decide to apply the methods or uses for treating emotional blunting described herein.

[0214] In some aspects of the present invention, if a practicing physician or physician determines, by evaluation of the patient, that signs and symptoms of emotional blunting are present in the patient as a result of drug treatment, the physician may decide to apply the methods or uses for treating emotional blunting described herein, wherein the drug is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0215] In some aspects of the present invention, if a practicing physician or doctor determines, by evaluation of the patient, that signs and symptoms of emotional blunting are present in the patient as a result of drug treatment, the physician may decide to apply the methods or uses for treating emotional blunting described herein, wherein the drug is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, and the methods or uses for treating emotional blunting described herein include the following steps: 1) The step of discontinuing the medication that causes signs and symptoms of emotional blunting in the patient; and 2) The step of administering a therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to a patient in need.

[0216] In some embodiments, the present invention relates to a method for preventing or treating emotional blunting in a patient, wherein the patient has a medical history of exhibiting signs and symptoms of emotional blunting associated with a CNS disease or disorder or medical treatment for one or more CNS diseases or disorders, and the agent causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, and the method comprises the following steps: i) The step of evaluating the patient by a practicing physician or doctor, 1) Evaluation of the patient's medical history regarding signs and symptoms of emotional blunting; 2) Assessment of current signs or symptoms of emotional blunting; and / or 3) A step including an assessment of the risk that the patient will develop or worsen signs and / or symptoms of emotional blunting; ii) If the clinician in step 1) assesses that signs and symptoms of emotional blunting are present or at risk of developing such signs and symptoms, administer a therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to the patient in need; and iii) In step 2), depending on the underlying CNS disorder, the practitioner or physician determines whether to administer one or more additional drugs for the treatment of the one or more CNS disorders or to discontinue one or more drugs for the treatment of the one or more CNS disorders and replace them with an effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting according to any one embodiment, wherein a practitioner or physician decides to apply the use for treating emotional blunting according to the prior embodiments when, by evaluation of the patient, it is confirmed that signs and symptoms of emotional blunting are present in the patient, or that the risk of emotional blunting has been established based on the use of the agent for the treatment of CNS disease or disorder, and optionally such treatment includes the following steps: 1) If the CNS disorder or disorder is a mood disorder and the drug is an antidepressant, the first step is to continue the drug, and the drug is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof; or 2) If the CNS disorder or condition is selected from the group of mental disorders, such as schizophrenia, schizoaffective disorder, schizophrenia-like disorder, catatonia, delusional disorder, and substance use disorder, the first step is to continue the use of antidepressants or mood stabilizers, or to maintain the administration of non-antidepressant or non-mood stabilizer medications for the treatment of schizophrenia or psychosis, if such medications have been used to treat the CNS disorder or condition.

[0218] The second step is to administer a therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to the patient in need.

[0219] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting according to any one of the prior embodiments, wherein a practitioner or physician, upon assessment of the patient, confirms that signs and symptoms of emotional blunting are present in the patient, and decides to apply the use for treating emotional blunting according to the prior embodiments, optionally including the following steps: a) Steps of discontinuing the drug other than 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof; and b) The step of administering a therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to a patient in need.

[0220] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting according to any one of the prior embodiments, wherein the agent is administered for the prevention or treatment of one or more CNS diseases or disorders or their signs and symptoms, and the agent is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, and the emotional blunting has been reported to be (1) a result of the CNS disease or disorder, (2) a result of an inadequate response to the medical treatment, or (3) caused by an inadequate response to the medical treatment for the CNS disease or disorder.

[0221] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting or its signs and symptoms in patients.

[0222] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting or its signs and symptoms in a patient, wherein the patient is experiencing signs and symptoms of emotional blunting.

[0223] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting or its signs and symptoms in a patient, wherein the patient has experienced or has a history of emotional blunting, and the agent causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0224] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting or its signs and symptoms in a patient, wherein the patient has experienced emotional blunting or has a medical history of signs and symptoms of emotional blunting associated with the administration of a drug, and the drug causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0225] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting in a patient, wherein the patient has experienced emotional blunting or has a medical history of signs and symptoms of emotional blunting resulting from the administration of a drug, and the drug causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting in a patient, wherein the patient has experienced emotional blunting or has a history of signs and symptoms of emotional blunting resulting from the administration of an agent for treating one or more CNS diseases or disorders, and the agent causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0227] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting in a patient, wherein the patient has experienced emotional blunting or has a history of signs and symptoms of emotional blunting resulting from the administration of a drug in an appropriate dose, and the drug causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting in a patient, wherein the patient has not received any treatment for a CNS disorder or disorder prior to experiencing the signs and / or symptoms of emotional blunting.

[0229] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting in a patient, wherein the patient has a medical history of signs and symptoms of emotional blunting resulting from the administration of a drug, and the drug causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, and the drug causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting in a patient, wherein the patient has a medical history of exhibiting signs and symptoms of emotional blunting associated with a CNS disease or disorder or the medical treatment of one or more CNS diseases or disorders, and the agent causing the signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, and this use comprises the following steps: i) The step of evaluating the patient by a practicing physician or doctor: 1) Evaluation of the patient's medical history regarding signs and symptoms of emotional blunting; 2) Assessment of current signs or symptoms of emotional blunting; and 3) A step including an assessment of the risk that the patient will develop or worsen signs and / or symptoms of emotional blunting; ii) If the clinician in step 1) assesses that signs and symptoms of emotional blunting are present or that there is a risk of developing such signs and symptoms of emotional blunting, administer a therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to the patient in need; and iii) In step 2), depending on the underlying CNS disorder, the practitioner or physician determines whether to administer one or more additional drugs for the treatment of the one or more CNS disorders or to discontinue one or more drugs for the treatment of the one or more CNS disorders and replace them with an effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments, the appropriate dose of the agent is the dose indicated on the label of the agent. In some embodiments, the method or use of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof of the present invention refers to an appropriate dose of the agent, where the agent is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, and the appropriate dose of the agent is the dose indicated on the label of the agent, and is selected from any one of the doses for effective treatment indicated on the label of the agent.

[0232] In some embodiments, the emotional blunting is observed in connection with or as a result of the administration of a drug, and includes the following steps: 1) Steps for discontinuing the drug; and 2) The step of administering a therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to a patient in need.

[0233] In some embodiments, the emotional blunting is observed in connection with or as a result of the administration of a drug, and includes the following steps: 1) Discontinuation of the aforementioned drugs for the treatment of CNS diseases or disorders; and 2) The step of administering a therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to a patient in need.

[0234] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the treatment of CNS disorders or disorders, wherein the agent is intended for use in patients who have previously taken another agent for the treatment of the said disorder or disorder that has been discontinued, reduced, or had to be discontinued due to emotional blunting.

[0235] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to the above embodiments, wherein the CNS disease or disorder is depression such as MDD.

[0236] In some embodiments, methods for use in the prevention or treatment of emotional blunting, or 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, are for the prevention of emotional blunting in patients.

[0237] In some embodiments, a method for use in the prevention or treatment of emotional blunting, or 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, is for treating emotional blunting in a patient. In some embodiments, the emotional blunting is related to a CNS disorder or disorder. In some embodiments, the emotional blunting is related to an underlying CNS disorder or disorder.

[0238] In some embodiments, the emotional blunting is observed in connection with or as a result of the administration of a drug, the drug being for the treatment of one or more CNS diseases or disorders or their signs and symptoms, and not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or any pharmaceutically acceptable salt thereof. In some embodiments, the emotional blunting is reported by the patient. In some embodiments, the emotional blunting is diagnosed by a practicing physician or doctor. In some embodiments, the emotional blunting is reported by the patient as being caused by an inadequate response to medical treatment for a CNS disease or disorder.

[0239] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting according to any one of the prior embodiments, wherein the agent is provided for the treatment of one or more CNS diseases or disorders, the CNS diseases or disorders being selected from the group consisting of: MDD, MDE, PTSD, schizophrenia, cognitive impairment, Parkinson's disease, autism, vascular dementia, and multiple system atrophy.

[0240] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting according to any one of the prior embodiments, wherein the agent has an enhancing effect on serotonergic transmission and is optionally selected from the SSRI or SNRI class.

[0241] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of emotional blunting according to any one of the prior embodiments, wherein the agent reduces dopaminergic transmission and is optionally selected from typical or atypical antipsychotics.

[0242] In some embodiments, the emotional blunting is diagnosed by a general practitioner or physician evaluating the patient, and the evaluation includes the following steps: a) Step of initiating a conversation with the patient; b) The step of asking the question, “Have you experienced such emotional impacts in the past six weeks?” and c) A step of evaluating the response to question b) and determining whether symptoms or signs of emotional blunting are present in the patient.

[0243] In some embodiments, the emotional blunting is diagnosed by a general practitioner or physician evaluating the patient, and the evaluation includes the following steps: a) A step of initiating a conversation with the patient and explaining the general emotional effects of emotional blunting; b) The step of asking the question, “Have you experienced such emotional impacts in the past six weeks?” and c) A step of evaluating the response to question b) and determining whether symptoms or signs of emotional blunting are present in the patient.

[0244] In some embodiments, the emotional blunting is diagnosed by a general practitioner or physician evaluating the patient, and the evaluation includes the following steps: a) A step of initiating a conversation with the patient and explaining the general emotional effects of emotional blunting, which may include information from the patient such as: “The emotional effects vary, but may include, for example, feeling emotionally ‘numb’ or ‘blunt’ in some way; a lack of positive or negative emotions; feeling disconnected from the world around you; or ‘not caring at all’ about things that used to care about.” b) The step of asking the question, “Have you experienced such emotional impacts in the past six weeks?” and c) A step of evaluating the patient's response to question b) to determine whether symptoms or signs of emotional blunting are present.

[0245] In some embodiments, if the patient's answer to the question asked in step b) is "yes," step c) of the practitioner's or physician's evaluation leads to the conclusion that emotional blunting is present.

[0246] In some embodiments, the emotional blunting is diagnosed by a general practitioner or physician evaluating the patient, and the evaluation includes the following steps: a) The step of explaining to the patient: “The emotional effects can vary, but may include, for example, feeling emotionally ‘numb’ or ‘blunted’ in some way; a lack of positive or negative emotions; feeling disconnected from the world around you; or ‘not caring at all’ about things that you used to care about.” b) The step of asking the question, “Have you experienced such emotional impacts in the past six weeks?” and c) Evaluating the response to question b), and determining if the patient answers "yes" to question b), that symptoms or signs of emotional blunting are present in the patient.

[0247] In some embodiments, steps a) to c) of the evaluation of the practicing physician or doctor may be supplemented or replaced by an evaluation using the ODQ scale and the ODQ total score or an equivalent evaluation, the ODQ total score of which is calculated based on the ODQ guidelines.

[0248] In some embodiments, steps a) to c) of the evaluation of the practicing physician or doctor may be supplemented or replaced by an evaluation using the ODQ scale or an equivalent evaluation, wherein the total ODQ score is 30 points or higher, and the total ODQ score is calculated based on the ODQ guidelines.

[0249] In some embodiments, steps a) to c) of the evaluation of the practicing physician or doctor may be supplemented or replaced by an evaluation using the ODQ scale or an equivalent evaluation, wherein the total ODQ score is 40 points or higher, and the total ODQ score is calculated based on the ODQ guidelines.

[0250] In some embodiments, steps a) to c) of the evaluation of the practicing physician or doctor may be supplemented or replaced by an evaluation using the ODQ scale or an equivalent evaluation, wherein the total ODQ score is 50 points or higher, and the total ODQ score is calculated based on the ODQ guidelines.

[0251] In some embodiments, steps a) to c) of the evaluation of the practicing physician or doctor may be supplemented or replaced by an evaluation using the ODQ scale or an equivalent evaluation, wherein the total ODQ score is 70 points or higher, and the total ODQ score is calculated based on the ODQ guidelines.

[0252] In some embodiments, steps a) to c) of the evaluation of the practicing physician or doctor may be supplemented or replaced by an evaluation using the ODQ scale or an equivalent evaluation, wherein the total ODQ score is 90 points or higher, and the total ODQ score is calculated based on the ODQ guidelines.

[0253] In some embodiments, the emotional blunting is observed in combination with a total MEI score of approximately 45 or less, and the total MEI score is evaluated according to the MEI guidelines.

[0254] In some embodiments, emotional blunting is observed in combination with an MEI total score of approximately 40 or less, the MEI total score being evaluated according to the MEI guidelines.

[0255] In some embodiments, the emotional blunting is observed in combination with an MEI total score of approximately 30 or less, and the MEI total score is evaluated according to the MEI guidelines.

[0256] In some embodiments, the emotional blunting is observed in combination with an SDS total score of approximately 15 or more, the SDS total score being calculated according to the SDS guidelines.

[0257] In some embodiments, the emotional blunting is seen in combination with a total SDS score of about 20 or more, and the total SDS score is calculated according to the guidelines of the SDS.

[0258] In some embodiments, the emotional blunting is seen in combination with a total SDS score of about 25 or more, and the total SDS score is calculated according to the guidelines of the SDS.

[0259] In some embodiments, steps a) to c) of the evaluation by the general practitioner or physician can be supplemented or replaced by an evaluation using the SANS scale or an equivalent evaluation, and the relevant score is calculated based on the guidelines of the SANS.

[0260] In some embodiments, steps a) to c) of the evaluation by the general practitioner or physician can be supplemented or replaced by an evaluation using the CAINS scale or an equivalent evaluation, and the relevant score is calculated based on the guidelines of the CAINS.

[0261] In some embodiments, steps a) to c) of the evaluation by the general practitioner or physician can be supplemented or replaced by an evaluation using the BNSS scale or an equivalent evaluation, and the relevant score is calculated based on the guidelines of the BNSS.

[0262] In some embodiments, steps a) to c) of the evaluation by the general practitioner or physician can be supplemented or replaced by an evaluation using the PANSS scale or an equivalent evaluation, and the relevant score is calculated based on the guidelines of the PANSS.

[0263] In some embodiments, steps a) to c) of the evaluation by the general practitioner or physician can be supplemented or replaced by an evaluation using the RSEB scale or an equivalent evaluation, and the relevant score is calculated based on the guidelines.

[0264] In some embodiments, steps a) to c) of the assessment by the practicing physician or physician may be supplemented or replaced by an assessment according to the definitions of paralysis and avoidance in the Diagnostic and Statistical Manual of the American Psychiatric Association or an equivalent assessment.

[0265] In some embodiments, steps a) to c) of the assessment by the practicing physician or physician may be supplemented or replaced by an assessment according to the definitions of paralysis and avoidance in the Diagnostic and Statistical Manual of the American Psychiatric Association, or an equivalent assessment, which includes the following steps: i) The step of giving the patient a questionnaire about one or more of the following experiences: 1) Limitation of the range of emotions, e.g., inability to feel love; and 2) A significant decrease in interest in important activities (these important activities can be defined as activities that were previously of interest and important to the patient); and ii) A step of evaluating the questionnaire to determine whether symptoms or signs of emotional blunting are present in the patient.

[0266] In some embodiments, steps a) to c) of the assessment by the practicing physician or physician may be supplemented or replaced by an assessment according to the definitions of paralysis and avoidance in the Diagnostic and Statistical Manual of the American Psychiatric Association, or an equivalent assessment, which includes the following steps: i) The step of giving the patient a questionnaire that includes one or more questions in accordance with the definitions of paralysis and avoidance in the Diagnostic and Statistical Manual of the American Psychiatric Association, including one or more of the following items: 1) Efforts to avoid thoughts or feelings related to trauma; 2) Efforts to avoid activities or situations that trigger traumatic memories; 3) Inability to recall important specific examples of the trauma (psychogenic amnesia); 4) A significant decrease in interest in important activities (in young children, this may include loss of recently acquired developmental skills such as toilet training or language skills); 5) A feeling of separation or alienation from others; 6) Limitation of the range of emotions, for example, inability to feel love; 7) A sense that the future has been shortened, for example, not expecting a career, marriage, children, or longevity; and ii) A step of evaluating the questionnaire to determine whether symptoms or signs of emotional blunting are present in the patient.

[0267] In some embodiments, the methods or uses or treatments described herein are rapid-acting methods or uses for the treatment of emotional blunting. In some embodiments, the methods or uses described herein are rapid-acting methods or uses for the treatment of emotional blunting, and the reduction of signs or symptoms is detectable by the patient within one week or assessed by a physician, for example, on a questionnaire completed by the patient. In some embodiments, the methods or uses described herein are rapid-acting methods or uses for the treatment of emotional blunting, and the reduction of signs or symptoms is detectable by the patient within two weeks or assessed by a physician, for example, on a questionnaire completed by the patient. In some embodiments, the methods or uses described herein are rapid-acting methods or uses for the treatment of emotional blunting, and the reduction of signs or symptoms is detectable by the patient within four weeks or assessed by a physician, for example, on a questionnaire completed by the patient.

[0268] In some embodiments, the methods or uses described herein are applied, and the total ODQ score decreases by about 6 to about 10 points within about one week of administration of the therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0269] In some embodiments, the methods or uses described herein are applied, and the total ODQ score decreases by about 6.5 to about 13 points within about one week of administration of the therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0270] In some embodiments, the methods or uses described herein are applied, and the total ODQ score decreases by about 15 to about 25 points within about 4 weeks of administration of the therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0271] In some embodiments, the methods or uses described herein are applied, and the total ODQ score decreases by about 17.6 to about 24.8 points within about four weeks of administration of the therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0272] In some embodiments, the methods or uses described herein are applied, and the total ODQ score decreases by about 25 to about 30 points within about 8 weeks of administration of the therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0273] In some embodiments, the methods or uses described herein are applied, and the total ODQ score decreases by about 26 to about 29.8 points within about 8 weeks of administration of the therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0274] In some embodiments, the methods or uses described herein are applied, and the total ODQ score decreases by about 30 points or more within about 8 weeks of administration of the therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0275] In some embodiments, the methods or uses described herein are applied, and the MEI total score increases by about 18 to about 30 points within about four weeks of administration of the therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0276] In some embodiments, the method or use described herein is applied, and the total MEI score increases by about 18.8 points to about 28.3 points within about 4 weeks of administration of a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0277] In some embodiments, the method or use described herein is applied, and the total MEI score increases by about 28 points to about 40 points within about 8 weeks of administration of a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0278] In some embodiments, the method or use described herein is applied, and the total MEI score increases by about 28.9 points to about 39.7 points within about 8 weeks of administration of a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0279] In some embodiments, the method or use described herein is applied, and the total MEI score increases by about 40 points or more within about 8 weeks of administration of a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0280] In some embodiments, the method or use described herein is applied, and the total SDS score decreases by about 5 points to about 10 points within about 8 weeks of administration of a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0281] In some embodiments, the method or use described herein is applied, and the total SDS score decreases by about 5.9 points to about 9.5 points within about 8 weeks of administration of a therapeutically effective amount of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0282] In some embodiments, the methods or uses described herein are applied, and the SDS total score decreases by about 10 points or more about 8 weeks after administration of the therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

[0283] In some embodiments, the methods or uses described herein are applied, and about 50% of the patients answer "no" to a screening question described in the aspects and embodiments herein as item b) and read as "Have you experienced such an emotional impact in the last 6 weeks?", and the said response from the patients is "no" after daily administration of at least 10 mg / day of a therapeutically effective dose of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt.

[0284] In some embodiments, the emotional blunting has been reported or diagnosed at least once prior to the initiation of any medical procedure.

[0285] In some embodiments, the emotional blunting is reported or diagnosed at least once before or after the commencement of any medical procedure.

[0286] In some embodiments, the emotional blunting is reported or diagnosed at least once after the initiation of any medical procedure.

[0287] In some embodiments, the emotional blunting has been reported or diagnosed at least once prior to the initiation of any medication.

[0288] In some embodiments, the emotional blunting has been reported or diagnosed at least once before or after the initiation of any drug.

[0289] In some embodiments, the emotional blunting is reported or diagnosed at least once after the initiation of any drug.

[0290] In some embodiments, the methods or uses described herein include the selection of the CNS disease or disorder from the group consisting of MDD, MDE, PTSD, schizophrenia, cognitive impairment, Parkinson's disease, autism, vascular dementia, and multiple system atrophy.

[0291] In some embodiments, the CNS disorder or condition is MDD. In some embodiments, the CNS disorder or condition is MDE. In some embodiments, the CNS disorder or condition is PTSD. In some embodiments, the CNS disorder or condition is schizophrenia. In some embodiments, the CNS disorder or condition is Parkinson's disease. In some embodiments, the CNS disorder or condition is autism. In some embodiments, the CNS disorder or condition is vascular autism. In some embodiments, the CNS disorder or condition is vascular dementia. In some embodiments, the CNS disorder or condition is multiple system atrophy ("MSA"). In some embodiments, the CNS disorder or condition is cognitive impairment. In some embodiments, the cognitive impairment is associated with Alzheimer's disease or schizophrenia.

[0292] In some embodiments, the cognitive impairment is diagnosed by a practicing physician or doctor.

[0293] In some embodiments, the cognitive impairment is diagnosed by a physician, therapist, or physical therapist using a scale similar to the DSST. In some embodiments, the cognitive impairment is reported by the patient.

[0294] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof according to any one of the prior embodiments, or to the use according to any one of the prior embodiments, wherein the patient has not received any treatment for a CNS disorder or disorder prior to experiencing the signs and / or symptoms of emotional blunting.

[0295] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof administered by any of the uses or methods disclosed herein is a crystalline salt.

[0296] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof administered by any of the uses or methods disclosed herein is a crystalline salt, which is selected from the group consisting of hydrobromide (α), hydrobromide (β), and hydrobromide (γ).

[0297] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof administered by any of the uses or methods disclosed herein is a crystalline salt, which is selected from the group consisting of DL, D-, and L-lactate addition salts.

[0298] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof administered by any of the uses or methods disclosed herein is a crystalline salt, which is selected from the group consisting of DL, D-, and L-pyropyroglutamates.

[0299] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof administered by any of the uses or methods disclosed herein is a crystalline salt, wherein the crystalline salt has major XRPD peaks at 5.85±0.2, optionally ±0.1(°2θ), 9.30±0.2, optionally ±0.1(°2θ), 17.49±0.2, optionally ±0.1(°2θ), and 18.58±0.2, optionally ±0.1(°2θ); 6.89±0.2, optionally ±0.1 The group is selected from the following: hydrobromide (β) with major XRPD peaks at (°2θ), 9.73±0.2, ±0.1(°2θ) by arbitrary selection, 13.78±0.2, ±0.1(°2θ) by arbitrary selection, and 14.62±0.2, ±0.1(°2θ) by arbitrary selection; hydrobromide (γ) with major XRPD peaks at 11.82±0.2, ±0.1(°2θ) by arbitrary selection, 16.01±0.2, ±0.1(°2θ) by arbitrary selection, 17.22±0.2, ±0.1(°2θ) by arbitrary selection, and 18.84±0.2, ±0.1(°2θ) by arbitrary selection.

[0300] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof administered by any of the uses or methods disclosed herein is a crystalline salt, which is a hydrobromide (β) having major XRPD peaks at 6.89±0.2, optionally ±0.1(°2θ), 9.73±0.2, optionally ±0.1(°2θ), 13.78±0.2, optionally ±0.1(°2θ), and 14.62±0.2, optionally ±0.1(°2θ). In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof administered by any of the uses or methods disclosed herein is a crystalline salt, and the crystalline salt is 6.01±0.2, optionally ±0.1(°2θ), 10.10±0.2, optionally ±0.1(°2θ), 10.32±0.2, optionally ±0.1(°2θ), 12.06±0.2, optionally ±0.1(°2θ), 12.84±0.2, optionally ±0.1(°2θ), 13.08±0.2, optionally ±0.1(°2θ), and 13.58±0.2, optionally ±0.1(°2θ). The following group is selected: DL-lactate salts having a major XRPD peak; L-lactate salts having a major XRPD peak at 5.33±0.2, optionally ±0.1(°2θ), 9.75±0.2, optionally ±0.1(°2θ), 10.10±0.2, optionally ±0.1(°2θ), and 14.63±0.2, optionally ±0.1(°2θ); or D-lactate salts having a major XRPD peak at 5.33±0.2, optionally ±0.1(°2θ), 9.75±0.2, optionally ±0.1(°2θ), 10.10±0.2, optionally ±0.1(°2θ), and 14.63±0.2, optionally ±0.1(°2θ).

[0301] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof administered by any of the uses or methods disclosed herein is a crystalline salt, wherein the crystalline salt has major XRPD peaks at 10.72±0.2, optionally ±0.1(°2θ), 12.14(°2θ)±0.2, optionally ±0.1, 16.22±0.2, optionally ±0.1(°2θ), and 18.59±0.2, optionally ±0.1(°2θ); 10.72±0.2, optionally The group is selected from the following: D-pyroglutamic acid having major XRPD peaks at ±0.1(°2θ), 12.14(°2θ), 16.22±0.2, ±0.1(°2θ) by arbitrary selection, and 18.59±0.2, and ±0.1(°2θ) by arbitrary selection; and DL-pyroglutamic acid having major XRPD peaks at 6.16±0.2, ±0.1(°2θ) by arbitrary selection, 9.25±0.2, ±0.1(°2θ) by arbitrary selection, 17.68±0.2, ±0.1(°2θ) by arbitrary selection, and 18.59±0.2, and ±0.1(°2θ) by arbitrary selection.

[0302] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, administered by any of the uses or methods disclosed herein, is administered to the patient in doses of about 1 mg to about 50 mg per day, preferably about 5 mg, about 10 mg, or about 20 mg.

[0303] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, administered by any of the uses or methods disclosed herein, is administered to the patient in doses of about 10 mg or about 20 mg per day.

[0304] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof administered by any use or method disclosed herein is administered to the patient at a dose of about 10 mg per day during the first week, i.e., from day 1 to about day 6 or about day 7, and after the first week, i.e., at a dose of about 10 mg or about 20 mg per day, in cases where such administration of the 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is required for the patient.

[0305] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof according to any one of the prior embodiments for use in the prevention or treatment of emotional blunting, wherein the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is a crystalline salt, which is selected from the group consisting of hydrobromide (α), hydrobromide (β), hydrobromide (γ), DL-, D-, or L-lactate addition salts, or DL-, D-, or L-pyroglutamate salts, in a daily dose of about 10 mg or about 20 mg, wherein the patient is administered about 10 mg per day for about one week, and the dose is maintained at about 10 mg per day thereafter, or the dose is increased, according to the practice or physician.

[0306] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof according to any one of the prior embodiments for use in the prevention or treatment of emotional blunting, wherein the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is vortioxetine in a daily dose of about 10 mg or about 20 mg, the patient being administered about 10 mg per day for about one week, and the dose being maintained at about 10 mg per day thereafter, or preferably increased to about 20 mg per day, according to the practicing physician or doctor.

[0307] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered to the patient by any of the uses or methods disclosed herein, and the administration of the 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is carried out by any suitable route of administration.

[0308] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered to the patient by any of the uses or methods disclosed herein, and the administration of the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is carried out by any suitable route of administration, which may be subcutaneous, intravenous, sublingual, or oral.

[0309] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered to the patient by any of the uses or methods disclosed herein, the administration of the 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is carried out by any suitable route of administration, the route of administration being oral.

[0310] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered to the patient by any of the uses or methods disclosed herein, and the administration of the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is carried out by any suitable route of administration, the route of administration being oral in the form of a tablet. In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered to the patient by any of the uses or methods disclosed herein, and the administration of the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is carried out by any suitable route of administration, the route of administration being oral in the form of a tablet containing the following components:

[0311] [Table 7]

[0312] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered to the patient by any of the uses or methods disclosed herein, the administration of the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is carried out by any suitable route of administration, the route of administration being oral administration in the form of a tablet containing one, one or more, or all of the following components.

[0313] [Table 8]

[0314] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered to the patient by any of the uses or methods disclosed herein, the administration of the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is carried out by any suitable route of administration, which is orally in the form of oral drops, as described in International Publication No. 2010 / 121621 (which is incorporated herein by reference in its entirety), containing DL-, D-, or L-lactates of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine.

[0315] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered to the patient by any of the uses or methods disclosed herein, wherein the administration of the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is carried out by any suitable route of administration, which is orally in the form of oral drops, which are liquid pharmaceutical formulations containing a salt of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine selected from 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine DL-lactated salt, 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine L-lactated salt, and 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine D-lactated salt.

[0316] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered to the patient by any of the uses or methods disclosed herein, the administration of the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is carried out by any suitable route of administration, the route of administration being oral in the form of a sublingual composition.

[0317] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered to the patient by any of the uses or methods disclosed herein, the administration of the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is carried out by any suitable route of administration, the route of administration being oral administration in the form of a sublingual gel composition described in International Publication No. 2016 / 180870 (which is incorporated herein by reference in its entirety).

[0318] In some embodiments, the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered to the patient by any of the uses or methods disclosed herein, the administration of the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is carried out by any suitable route of administration, the route of administration being oral administration in the form of a sublingual gel composition described in International Publication No. 2016 / 180870 (above), comprising 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine DL-, D-, or L-pyropyroglutamate and at least one pharmaceutically acceptable carrier or diluent.

[0319] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention, reduction, or treatment of emotional blunting in patients.

[0320] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to the above embodiments, wherein the patient suffers from a CNS disease or disorder.

[0321] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of the above embodiments, wherein the patient experiences emotional blunting as part of a CNS disorder or disorder.

[0322] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of the above embodiments, wherein the patient has previously taken or is currently taking an agent for the treatment of the CNS disease.

[0323] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of the above embodiments, wherein the agent causes symptoms and signs of emotional blunting, and the agent is discontinued or must be discontinued due to emotional blunting.

[0324] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of the above embodiments, wherein the CNS disorder or disorder is selected from mental disorders such as psychosis, schizophrenia, schizoaffective disorder, schizophrenia-like disorder, catatonia, and delusional disorder; mood disorders such as bipolar disorder, cyclothymic disorder, major depression, dysthymia, and premenstrual dysphoric disorder; and substance use disorders.

[0325] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of the above embodiments, wherein the CNS disease or disorder is selected from depression, cognitive impairment, schizophrenia, psychosis, Parkinson's disease, autism, vascular dementia, and multiple system atrophy, including PTSD, MDD and MDE.

[0326] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of the above embodiments, wherein the CNS disease or disorder is selected from MDD and schizophrenia.

[0327] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of the above embodiments, wherein the agent is an SSRI or SNRI.

[0328] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of the above embodiments, wherein the CNS disease or disorder is selected from MDD and schizophrenia, and the agent is an SSRI or SNRI.

[0329] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of the above embodiments, wherein the agent is selected from escitalopram, fluoxetine, paroxetine, sertraline, venlafaxine, desvenlafaxine, and duloxetine.

[0330] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of the above embodiments, wherein the patient has an ODQ total score greater than 30, for example, greater than 40, greater than 50.

[0331] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of the above embodiments, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrobromide, lactate, and pyroglutamate.

[0332] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to embodiments, wherein the pharmaceutically acceptable salt is selected from hydrobromide (α), hydrobromide (β), and hydrobromide (γ).

[0333] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of the prior embodiments, wherein 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in unit doses of about 5 mg, about 10 mg, or about 20 mg of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine (calculated as free base).

[0334] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of the embodiments described above, wherein 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in doses of about 5 mg / day, about 10 mg / day, or about 20 mg / day of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine (calculated as free base).

[0335] In some embodiments, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of the above embodiments, wherein 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as an oral tablet or oral drop.

[0336] Those skilled in the art will be able to recognize or confirm equivalents of specific embodiments of the invention described herein by means of routine experiments. Such equivalents are considered to fall within the scope of the invention. The present invention may include the following embodiments. [1] 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention, reduction, or treatment of emotional blunting in patients. [2] 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient suffers from a CNS disease or disorder. [3] 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to claim 1 or 2, wherein the patient is experiencing emotional blunting as part of a CNS disorder or disability. [4] 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to claim 2 or 3, wherein the patient has previously taken or is currently taking an agent for the treatment of the CNS disease. [5] 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to claim 4, wherein the drug causes symptoms and signs of emotional blunting, and the drug is discontinued or must be discontinued due to emotional blunting. [6] 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of claims 2 to 3, wherein the CNS disorder or disorder is selected from mental disorders such as psychosis, schizophrenia, schizoaffective disorder, schizophrenia-like disorder, catatonia, and delusional disorder; mood disorders such as bipolar disorder, cyclothymic disorder, major depressive disorder, dysthymia, and premenstrual dysphoric disorder; and substance use disorders. [7] 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of claims 4 to 5, wherein the CNS disease or disorder is selected from PTSD, depression (including major depressive disorder (MDD) and major depressive episode (MDE)), cognitive impairment, schizophrenia, psychosis, Parkinson's disease, autism, vascular dementia, and multiple system atrophy. [8] 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of claims 2 to 7, wherein the CNS disease or disorder is selected from major depressive disorder and schizophrenia. [9] 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of claims 4 to 5, wherein the agent is a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI).

[10] 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of claims 4 to 5, wherein the CNS disease or disorder is selected from major depressive disorder and schizophrenia, and the agent is a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI).

[11] 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of claims 9 to 10, wherein the agent is selected from escitalopram, fluoxetine, paroxetine, sertraline, venlafaxine, desvenlafaxine, and duloxetine.

[12] 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 11, wherein the patient has a total score greater than 30 on the Oxford Depression Scale (ODQ).

[13] 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 12, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrobromide, lactate, and pyroglutamate.

[14] 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to claim 13, wherein the pharmaceutically acceptable salt is selected from hydrobromide (α), hydrobromide (β), or hydrobromide (γ).

[15] 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 14, wherein 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of about 5 mg, about 10 mg, or about 20 mg of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine.

[16] 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 15, wherein 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in doses of approximately 5 mg / day, approximately 10 mg / day, or approximately 20 mg / day of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine.

[17] 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 16, wherein 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as an oral tablet or oral drop. [Examples]

[0337] General method International Publication Nos. 03 / 029232, 2007 / 144005, 2010 / 121621, and 2016 / 180870 (each incorporated herein in its entirety by reference) disclose the compound 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]-piperazine and its pharmaceutically acceptable salts, as well as methods for producing them.

[0338] General clinical trial methods In this 8-week open-label single-arm trial, patients switched directly from SSRIs / SNRIs to 8 weeks of treatment with vortioxetine (10 mg / day for 1 week, followed by 10–20 mg / day for 7 weeks, variable dose).

[0339] This trial included outpatients aged 18–65 years with a primary diagnosis of MDD (according to DSM-5) and a current depressive episode less than 12 months prior. Eligibility required patients who had shown an inadequate (i.e., partial) response to approved doses of SSRI or SNRI monotherapy (SSRIs: escitalopram, paroxetine, sertraline; SNRIs: duloxetine, and venlafaxine) at least 6 weeks prior to the screening visit. Baseline scores had to include a MADRS total score (severity of depression) between 21 and 29, and an ODQ total score (severity of emotional blunting) of 50 or greater. In addition, all patients had to answer "yes" to the standardized “absolute criteria” screening questions for emotional blunting developed by Price et al (2012) (above): “Emotional effects vary, but may include, for example, feeling emotionally “numb” or “blunted” in some way; lack of positive or negative emotions; feeling disconnected from the world around you; or “not caring at all” about things you used to care about.” “Have you experienced such emotional effects in the last six weeks?” All patients had to be candidates for medication change based on their own opinion and the opinion of the principal investigator.

[0340] Patients with a current primary psychiatric diagnosis other than MDD, or those who had abused any substance within six months prior to the start of the study, were excluded, as were patients with an inadequate response to a series of treatments with two previous antidepressants at appropriate doses and durations. Other key exclusion criteria included intellectual disability, pregnancy, and suicide risk.

[0341] This trial was conducted between February 2019 and February 2020 at a total of 23 sites in France, Spain, Italy, and Lithuania, in accordance with the Principles of Good Clinical Practice (ICH 2016) and the Declaration of Helsinki (World Medical Association, 2002), and was approved by the local ethics committee of each trial site. Eligible patients submitted written informed consent before participating in any trial procedure. This trial is registered with ClinicalTrials.gov (NCT03835715) and the EU Clinical Trials Register (EudraCT number 2017-004829-33).

[0342] The following “assays” describe in general terms a study conducted to evaluate the efficacy of 10 mg or 20 mg of vortioxetine treatment on emotional function, i.e., the effect of vortioxetine on emotional blunting. One aspect of the study concerned evaluating the efficacy of 10 mg or 20 mg of vortioxetine treatment on emotional function in MDD patients who were inadequately responsive to SSRI or SNRI treatment, which is known to induce some degree of emotional numbness or blunting in approximately 50% of patients. Several aspects of this objective included evaluating the efficacy of variable doses of vortioxetine, ranging from 10 to 20 mg, after 8 weeks of treatment on motivation and energy, family, social, and work functioning, cognitive function, and depressive symptoms, as well as evaluating the safety of the doses of vortioxetine and evaluating the symptoms of abrupt discontinuation of previous treatment with SSRI or SNRI and potential discontinuation after initiation of treatment with vortioxetine. An additional objective was to investigate the association between digital biomarkers or digital phenotypes and clinical features of the disease, including symptoms, function, and cognitive abilities; however, this objective was not investigated due to time constraints.

[0343] Assay I - Test Method Trials with the above objectives were designed as interventional, multinational, multicenter, open-label, and variable-dose trials.

[0344] This trial included an 8-week treatment period with vortioxetine, followed by a 4-week follow-up period for safety evaluation. Efficacy and safety were evaluated at weeks 0, 1, 4, and 8, and unscheduled visits for dose adjustments were permitted at any time during the treatment period.

[0345] Figure 1 shows an overview of the experimental design.

[0346] All assessments and evaluations of the different scales described in the following assays were performed by the principal investigator, i.e., a clinician.

[0347] Assay II - Registration Criteria Patients were males or females aged 18 to 65 years with a primary diagnosis of solitary or relapsing MDD and meeting the DSM-5® criteria for MDE. Furthermore, patients had a primary diagnosis of MDD, a current depressive episode lasting at least 12 months, and depressive symptoms corresponding to a MADRS total score greater than 21 but less than 29 after at least 6 weeks of monotherapy with an appropriate dose of an SSRI or SNRI. The patients also experienced emotional blunting, indicated by an ODQ total score greater than 50, and answered "yes" to the emotional blunting screening question ("Emotional effects can vary, but may include, for example, feeling emotionally “numb” or “blunted” in some way; lack of positive or negative emotions; feeling disconnected from the world around you; or “not caring at all” about things you used to care about." "Have you experienced such emotional effects in the last 6 weeks?"). Patients were enrolled if they themselves deemed it appropriate and / or if the principal investigator deemed them suitable for a change in antidepressant.

[0348] The patient has been treated with SSRI / SNRI monotherapy (citalopram, escitalopram, paroxetine, duloxetine, or venlafaxine) at a dose appropriate for their current MDE for at least 6 weeks, has an inadequate response, and is a candidate for a change of opinion from the investigator. Furthermore, the patient desires a change of treatment due to this inadequate response and has complained of emotional blunting as assessed by the emotional impact screening questionnaire (inclusion criterion 8) and an ODQ total score of 50 or higher. The severity of depressive symptoms as assessed by the MADRS total score must be between 22 and 28, corresponding to a level of moderate to severe depression.

[0349] The study planned to enroll approximately 150 patients. The trial consisted of an 8-week open-label, variable-dose treatment period. Safety follow-up was planned 30 days after the primary outcome visit or withdrawal visit.

[0350] Patient flow and baseline characteristics Of the 151 patients enrolled, 150 were treated; of these, 131 (87.3%) completed treatment, and 143 (95.3%) were included in the analysis. A total of 19 patients discontinued the study; the main reasons were adverse events (6 patients [4%]), loss of follow-up (6 patients [4%]), lack of efficacy (2 patients [1.3%]), protocol violation (3 patients [2%]), withdrawal of consent (1 patient [0.7%]), and “other reasons” (1 patient [0.7%]). The mean age of the patients was 47 years (SD=12), and 105 (70.0%) were female (Table 0). The mean MADRS total score at baseline was 25.5 (SD=1.7), and the mean ODQ total score was 89.4 (SD=15.1). Most patients (82%) switched from SSRIs (most commonly escitalopram) at the start of the trial, and 18% switched from SNRIs (mainly venlafaxine) (Table 0). Approximately half of the patients (51.4%) took a final dose of 20 mg of vortioxetine at week 8.

[0351] [Table 9]

[0352] Assay III - Switching patients from SSRIs or SNRIs to vortioxetine Patients who met the enrollment criteria were switched directly from SSRIs / SNRIs to 8 weeks of open-label vortioxetine. Vortioxetine (Lu AA21004) was administered as an oral tablet at a dose of 10 or 20 mg / day.

[0353] At baseline visits, all patients were switched from previous SSRI or SNRI treatment to open-label treatment with vortioxetine. The starting dose was 10 mg / day of vortioxetine for the first week. The dose may then be increased to 20 mg / day at visit 2 (week 1) or kept at 10 mg / day. The dose may be adjusted at scheduled and unscheduled visits (10 or 20 mg / day) according to patient response and the investigator's judgment.

[0354] Patients were instructed to receive 10 mg or 20 mg of vortioxetine at each visit, preferably taking the daily dose orally at the same time each day. They were instructed to take the initial dose of vortioxetine on the day following the administration of vortioxetine (day 1).

[0355] All patients received 10 mg / day in Week 1, starting the day after Visit 1 (Week 1). This study was designed as a variable-dose study, meaning that a visit to the principal investigator's clinic was mandatory after Week 1 (Visit 2), and patients could work with the principal investigator to decide whether to continue with a 10 mg / day vortioxetine dose or increase the dose to 20 mg / day from the day after Visit 2. Patients were also permitted to adjust their vortioxetine dose following scheduled or unscheduled visits to the principal investigator's clinic. Such unscheduled visits could be permitted at any time during the 7-week treatment. Thus, for the next 7 weeks, patients took 10–20 mg / day depending on their choice after Week 1, and Table 1 shows how many patients increased their dose after Week 1 and / or decreased or increased their dose at any point after Week 2, e.g., Week 2.5, Week 3, or Week 4, or at any other point before the end of Week 8.

[0356] [Table 10]

[0357] Most patients were switched from prior treatment with an SSRI or SNRI on one day to vortioxetine on another day, but in some cases, the dose of the SSRI or SNRI could be reduced before the first dose of vortioxetine.

[0358] Assay IV - Efficacy Evaluation Patient-reported signs and / or symptoms of emotional blunting were collected using one or more of the following standardized questionnaires: ODQ, MEI, or SDS.

[0359] Clinician assessments of signs and symptoms of emotional blunting were collected using one or more of the following standardized methods: MADRS, CGI-S, or CGI-I.

[0360] The efficacy of vortioxetine in the treatment of MDD was evaluated in a total of 14 short-term placebo-controlled trials (including a dedicated trial in the elderly); 3 short-term placebo-and-active trials; 1 long-term relapse prevention trial; and 6 long-term open-label extension trials. The clinical value of vortioxetine in the dose range of 5–20 mg / day was demonstrated compared to placebo using well-established efficacy measures with clinically appropriate effect sizes, clinically relevant results in responder-to-limiter ratio analysis, CGI-I scores, and improvements in health-related quality of life and overall function. Favorable effects of vortioxetine were observed in both short-term and long-term treatments and were independent of age, sex, race, BMI, and baseline disease characteristics. In addition, results from three large-scale randomized placebo-controlled trials in adult MDD patients showed consistent and clinically meaningful improvements in patients' cognitive abilities as assessed by the DSST and other objective and subjective measures of cognitive function. When measured using the UCSD Performance-based Skills Assessment (UPSA), an objective test of functional ability, significant and clinically meaningful improvements were observed in the ability to perform activities of daily living.

[0361] Assay V - Neuropsychological Test Neuropsychological tests used to assess the signs and symptoms of emotional blunting included, for example, the DSST.

[0362] Assay VI - Safety Evaluation Adverse events, including signs and symptoms of emotional blunting, may be recorded or reported using safety assessments commonly used in the reporting or diagnosis of adverse events.

[0363] Patient discontinuation of treatment due to adverse events related to emotional blunting may be recorded or reported according to the general method of the Measure of Signs and Symptoms ("DESS") that occurred as a result of discontinuation.

[0364] The safety of vortioxetine has been investigated in a large clinical trial program involving approximately 12,500 patients (including healthy volunteers) who received vortioxetine treatment. Based on adverse event reporting or diagnosis, evaluation of laboratory safety test values, ECG parameters (including QTc), vital signs, and body weight over time compared to placebo, vortioxetine was found to be safe and well-tolerated. The safety profiles of vortioxetine were found to be similar in adults and the elderly. Post-marketing experience, including approximately 2.7 million person-years of exposure, has confirmed the safety profile found in clinical trials.

[0365] A total of 71 patients (47.3%) reported TEAEs (Table 1A). The most common TEAEs (reported by over 2%) were nausea, headache, dizziness, vomiting, and diarrhea; one patient reported a serious adverse event ("missed miscarriage"). No patients died during the study. Six patients discontinued the study due to TEAEs; vomiting, nausea, and diarrhea were among the TEAEs that led to the withdrawal of two or more patients. The mean total DESS score was 1.9 (SD=3.8) at baseline and 2.2 (SD=4.2) at week 1, respectively.

[0366] [Table 11]

[0367] Assay VII - Other Evaluations The symptoms and signs of emotional blunting can be recorded through voice recordings and passively collected data from patients obtained through mobile phone applications such as Discovery by Mindstrong Version 2.2.

[0368] Endpoints of the assay VIII trial One particularly interesting endpoint of this trial was the baseline state of emotional blunting compared to baseline using the QDQ. The QDQ is a 26-item assessment scale that evaluates four aspects of emotional blunting and their likelihood of being attributable to antidepressant treatment.

[0369] Clinicians assessed the symptoms of depression using the MADRS.

[0370] [Table 12]

[0371] Assay IX - Statistical Methods Changes from baseline in the total ODQ score were analyzed using a mixed model for repeated measurement ("MMRM") approach, which included the interaction of site and week as fixed effects, baseline score as a continuous covariate, and weekly baseline score based on all available observations. Adjusted mean values, including standard errors ("SE") and p-values, were reported. Safety and tolerability were assessed using descriptive statistics.

[0372] The following set of analyses was used for the analysis: • Registered patient set ("APES") - all registered patients. • Treated patient set ("APTS") - all APES patients who took vortioxetine at least once. • Full Analysis Set ("FAS") - All patients with APTS who have a valid baseline assessment and at least one valid post-baseline assessment of the ODQ total score. • Efficacy analysis is based on FAS, and safety analysis is based on APTS.

[0373] Analysis of Assay X - Primary Endpoint

[0374] [Table 13]

[0375] Changes from baseline in the total ODQ score were analyzed using the MMRM approach. This model includes facility and week as fixed effects, baseline score as a continuous covariate, and interaction with weekly baseline scores. The analysis was based on all available observations. The adjusted mean values ​​of the model are shown in two-sided 95% confidence intervals ("Cl").

[0376] Analysis of the secondary endpoint of Assay XI

[0377] [Table 14]

[0378] For secondary endpoints, the same methodology described in the primary analysis was used. All analyses included baseline scores for specific endpoints as baseline covariates, except for CGI-I, which used baseline scores for CGI-S. The SDS total score was defined as the sum of three single items (work, social, and family).

[0379] Descriptive statistics For primary and secondary endpoints, descriptive statistics were presented as weekly absolute values ​​and, where relevant, changes from baseline. The distribution of the screening question regarding emotional impact is shown at week 8 with a two-sided 95% confidence interval.

[0380] Analysis of safety endpoints Summarize adverse events using descriptive statistics.

[0381] Descriptive statistics are presented using a frequency table of emergency symptoms for each DESS item, along with the total DESS score at baseline and week 1.

[0382] The following examples illustrate the results of the clinical trial method described above.

[0383] Example 1 - Assessment of emotional blunting by total ODQ score in MDD patients who experienced an insufficient response to SSRI or SNRI treatment and were switched to treatment with 10-20 mg of vortioxetine. Patients were registered and treated as described in Assays I-III.

[0384] Data were collected according to Assays IV-VIII and analyzed according to Assays IX-XI. Table 2 and Figure 2 below summarize the total ODQ scores (FAS, MMRM) from baseline to the end of the study at weeks 1, 4, and 8.

[0385] [Table 15]

[0386] The total ODQ score, which starts at approximately 90, decreased by approximately 30 points by week 8, resulting in a relative decrease of one-third in the ODQ score. Patients switched from SSRIs or SNRIs to vortioxetine felt relief from emotional blunting within the first week of switching to vortioxetine 10 mg treatment.

[0387] These data demonstrate that vortioxetine remarkably rapidly and efficiently alleviates these undesirable effects in this subgroup of patients experiencing emotional blunting due to an inadequate response to SSRI or SNRI treatment. It is noteworthy that the effect of vortioxetine on emotional blunting, as measured by the ODQ, was already significant after one week of treatment and continued to increase in magnitude over the following seven weeks. If the emotional blunting experienced by patients before participating in the study was caused by and a side effect of a prescribed antidepressant (either an SSRI or SNRI), the half-lives of these drugs clearly indicate that the side effect resolved within one to two weeks after discontinuation of treatment. Therefore, vortioxetine continued to improve symptoms of emotional blunting regardless of prior medication.

[0388] The baseline distribution of ODQ can be checked and reported as a histogram of a normal distribution pattern. See Figure 3.

[0389] Example 2 - Evaluation of ODQ domain scores in MDD patients who experienced an insufficient response to SSRI or SNRI treatment and were switched to treatment with 10-20 mg of vortioxetine. Patients were registered and treated as described in Assays I-III. Data were collected according to Assays IV-VIII and analyzed according to Assays IX-XI.

[0390] Tables 3 to 8 below summarize the ODQ domain scores: indifference (NC), emotional detachment (ED), decreased positivity (RD), generalized decline (RD), antidepressant use as a cause (AC), and the total ODQ score (FAS, MMRM) excluding AC from baseline to the end of the study at weeks 1, 4, and 8.

[0391] [Table 16]

[0392] [Table 17]

[0393] [Table 18]

[0394] [Table 19]

[0395] [Table 20]

[0396] [Table 21]

[0397] The data above clearly shows that the decline in the total ODQ score was not caused by one or more domains. The decline in the total ODQ score was observed in all domains of emotional blunting: NC, PR, ED, GR, and AC. AC indicated the extent to which patients considered symptoms related to the antidepressants they were taking.

[0398] When evaluating the total ODQ score excluding AC, the change from approximately 74 baseline to approximately 25 points at week 8 was equivalent to a relative change of approximately one-third, as reported in Example 1.

[0399] Example 3 - Evaluation of a screening questionnaire regarding emotional impact in MDD patients who experienced an insufficient response to SSRI or SNRI treatment and were switched to treatment with 10-20 mg of vortioxetine. Patients were registered and treated as described in Assays I-III. Data were collected according to Assays IV-VIII and analyzed according to Assays IX-XI.

[0400] As part of the patient registry described in Assay II, all patients enrolled in this study answered "yes" to the question: "Emotional effects can vary, but may include, for example, feeling emotionally numb or blunted in some way; lack of positive or negative emotions; feeling disconnected from the world around you; or becoming indifferent to things you used to care about. Have you experienced such emotional effects in the past six weeks?"

[0401] Table 9 below summarizes the number of patients who answered "no" to the same question after treatment with vortioxetine.

[0402] [Table 22]

[0403] The data above clearly shows that approximately 50% of patients who reported experiencing paralysis or hypotension-related emotional effects within the past six weeks while receiving SSRI or SNRI treatment now report no longer experiencing these effects eight weeks after receiving vortioxetine treatment.

[0404] Example 4 - Evaluation of MADRS in MDD patients who experienced an insufficient response to SSRI or SNRI treatment and were switched to treatment with 10-20 mg of vortioxetine. Patients were enrolled and treated as described in Assays I-III. Data were collected according to Assays IV-VIII and analyzed according to Assays IX-XI. The MADRS scale indicated that lower scores were associated with less severe depression.

[0405] The baseline MADRS total score (FAS, MMRM) decreased by approximately 14 points over 8 weeks after switching patients to vortioxetine treatment, from approximately 25. A response, defined as a decrease of at least 50% from baseline in the MADRS total score (FAS, observed cases (OC)), was recorded in approximately 62% of patients at week 8. Remission, defined as a MADRS total score (FAS, OC) of 10 or less at week 8, was recorded in approximately 47%.

[0406] Example 5 - Evaluation of CGI-S in MDD patients who experienced an insufficient response to SSRI or SNRI treatment and were switched to treatment with 10-20 mg of vortioxetine. Patients were enrolled and treated as described in Assays I-III. Data were collected according to Assays IV-VIII and analyzed according to Assays IX-XI. On the CGI-S scale, lower scores indicated lower disease severity.

[0407] The CGI baseline score (FAS, MMRM) decreased by approximately 2 points from approximately 4.5, and the remission rate, as expressed by the CGI-S score (FAS, OC), was found to be approximately 48%, which is similar to the remission level survey results reported in Example 4.

[0408] Example 6 - Evaluation of MEI in MDD patients who experienced an insufficient response to SSRI or SNRI treatment and were switched to treatment with 10-20 mg of vortioxetine. Patients were enrolled and treated as described in Assays I-III. Data were collected according to Assays IV-VIII and analyzed according to Assays IX-XI. In the MEI score, a higher score indicates higher motivation and energy.

[0409] Table 10 below provides insights into the MEI total score.

[0410] [Table 23]

[0411] Starting at approximately 44, the total MEI score increased by approximately 34 points by week 8, resulting in a relative increase of over 85% in the MEI score. Patients who switched from SSRIs or SNRIs to vortioxetine reported increased levels of motivation and energy.

[0412] The baseline distribution of MEI can be checked and reported as a histogram of a normal distribution pattern. See Figure 4.

[0413] Example 7 - Evaluation of MEI subscores in MDD patients who experienced an insufficient response to SSRI or SNRI treatment and were switched to treatment with 10-20 mg of vortioxetine. Patients were enrolled and treated as described in Assays I-III. Data were collected according to Assays IV-VIII and analyzed according to Assays IX-XI. In the MEI score, a higher score indicates higher motivation and energy.

[0414] Tables 11-13 below provide insights into the total subscores of the MEI: the mental and cognitive energy score, the social motivation score, and the physical energy score (FAS, MMRM).

[0415] [Table 24]

[0416] [Table 25]

[0417] [Table 26]

[0418] The data above clearly shows that the increase in the total MEI score reported in Example 6 was not caused by a single MEI subscore. The increase in the total MEI score was observed in all three subscores: cognitive energy, social motivation, and physical energy.

[0419] Example 8 - Evaluation of SDS in MDD patients who experienced an insufficient response to SSRI or SNRI treatment and were switched to treatment with 10-20 mg of vortioxetine. Patients were enrolled and treated as described in Assays I-III. Data were collected according to Assays IV-VIII and analyzed according to Assays IX-XI. On the SDS scale, lower scores indicate higher overall function and less functional impairment.

[0420] Table 14 below provides insights into the total SDS score.

[0421] [Table 27]

[0422] The data above supports the idea that an 8-week treatment with vortioxetine leads to an improvement in the total disability score covering activities in the workplace, home, and social life.

[0423] Example 9 - Evaluation of SDS subscores in MDD patients who experienced an insufficient response to SSRI or SNRI treatment and were switched to treatment with 10-20 mg of vortioxetine. Patients were registered and treated as described in Assays I-III. Data were collected according to Assays IV-VIII and analyzed according to Assays IX-XI.

[0424] Tables 15-17 below provide insights into the SDS subscores: Work / School Score, Social Life Score, and Life / Home Responsibility Score (FAS, MMRM).

[0425] [Table 28]

[0426] [Table 29]

[0427] [Table 30]

[0428] The data above supports the idea that an 8-week treatment with vortioxetine leads to an improvement in overall impairment in workplace, home, and social settings.

[0429] Example 10 - Assessment of cognitive function using DSST scores in MDD patients who experienced an insufficient response to SSRI or SNRI treatment and were switched to treatment with 10-20 mg of vortioxetine. Patients were enrolled and treated as described in Assays I-III. Data were collected according to Assays IV-VIII and analyzed according to Assays IX-XI. In the DSST, higher scores indicated higher cognitive ability.

[0430] Table 18 below summarizes the effects of vortioxetine on cognitive abilities as measured by DSST (FAS, MMRM).

[0431] [Table 31]

[0432] The data above shows that vortioxetine has a cognitive-enhancing effect, increasing the baseline score of 46 DSSTs by 8 points.

[0433] Example 11 - Evaluation of the correlation between total MEI score and total ODQ score in MDD patients who experienced an insufficient response to SSRI or SNRI treatment and were switched to treatment with 10-20 mg of vortioxetine. Patients were registered and treated as described in Assays I-III. Data were collected according to Assays IV-VIII and analyzed according to Assays IX-XI.

[0434] Correlation analysis showed a correlation between vortioxetine and the total scores of MEI and ODQ (r=-0.778; p<0.001). Specifically, patients reported that less emotional blunting was associated with greater energy and motivation. Even after adjusting for improvements in the total MADR score, the association remained of moderate strength and highly statistical significance (r=-0.532; p<0.001). See Table 20 and Example 13.

[0435] Example 12 - Evaluation of the correlation between total ODQ score and total SDS score in MDD patients who experienced an insufficient response to SSRI or SNRI treatment and were switched to treatment with 10-20 mg of vortioxetine. Patients were registered and treated as described in Assays I-III. Data were collected according to Assays IV-VIII and analyzed according to Assays IX-XI.

[0436] Correlation analysis showed that vortioxetine was correlated with the total scores of SDS and ODQ (r=0.699, p<0.001). That is, the less emotional blunting there was, the higher the overall function. Even after adjusting for improvement in the total MADR score, the association remained of moderate strength and was highly significant (r=-0.5438; p<0.001). See Table 20 and Example 13.

[0437] Example 13 - Overview of Clinical Evaluation, Partial Correlation Analysis, and Mediation Analysis of Emotional Blurring At week 8, the mean change from baseline in the total ODQ score was -29.8 (SE=1.9; p<0.0001), showing a significant change from week 1 (Table 19; Figure 5). Significant changes were observed in all ODQ subdomains, ranging from -7.8 (SE=0.6; p<0.0001) (decreased self-esteem) to -4.7 (SE=0.5; p<0.0001) (emotional detachment) at week 8. The change from baseline in the "antidepressant as causative" domain was -5.1 (SE=0.5); excluding subscale scores from this domain from the total score in the primary analysis resulted in a change of -24.7 (SE=1.6) points from baseline to week 8. At week 8, 50% of all patients did not report emotional blunting on the standardized screening questions. A significant effect was observed in the MADRS Anhenamic Factor score from week 1 (-2.2; p<0.0001), and it increased up to week 4 (-5.9; p<0.0001) and week 8 (-8.9; p<0.0001).

[0438] [Table 32]

[0439] Other clinical evaluations Improvements in motivation and energy, as assessed using MEI, were substantial and significant in all subdomains: cognitive and mental energy, social motivation, and physical energy, starting as early as week 4 (Table 18; Figure 6). Significant improvements in cognitive ability (DSST) were observed as early as week 1 (4.3; p<0.0001) and continued to increase until week 8 (7.8; p<0.0001) (Table 18). Significant improvements in overall function from baseline to week 8, as measured by SDS, were observed in the total score and single items, most pronounced in the work / school domain (Table 19). Resolution of overall depressive symptoms, as measured by the MADRS total score, significantly improved from week 1 (-3.3; p<0.0001) and continued to increase until week 8 (13.8; p<0.0001). The response rate and remission rate at week 8, as measured by MADRS, were 61.8% and 46.6%, respectively.

[0440] Repeating the primary analysis with baseline adjustments and the change from baseline in the total MADRS score, the change in the total ODQ score from baseline to week 8 was -30.2 (SE=1.9), which decreased to -10.8 (SE=2.4) after adjusting for the change from baseline in the total MADRS score, representing 36% of the ODQ improvement that was unrelated to the observed improvement in MADRS.

[0441] Partial correlation analysis showed a strong positive correlation between changes in QDQ total score and SDS total score from baseline to week 8 (r=0.699; p<0.0001; Table 19). Furthermore, changes in ODQ were negatively correlated with changes in MEI total score (r=-0.778; p<0.0001). In other words, improvement in emotional blunting was associated with better functional outcomes as well as energy and motivation. After adjusting for improvements in MADRS total score, these associations remained of moderate strength and highly significant, with a partial r between changes in ODQ and SDS being 0.438 (p<0.0001) and a partial r between changes in ODQ and MEI being -0.532 (p<0.0001) (Table 20).

[0442] Mediation analysis further showed that 63.4% of the changes in the total SDS score explained by the changes in the total ODQ score were due to the direct effect of the improvement in ODQ after switching to vortioxetine, which could not be explained by the improvement in depressive symptoms (MADRS) (which accounted for 36.6% of the impact on the total SDS score) (Figure 7).

[0443] [Table 33]

Claims

1. A composition comprising 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the prevention, reduction, or treatment of emotional blunting in patients, A composition wherein the patient suffers from major depressive disorder (MDD).

2. The composition according to claim 1, wherein the patient is experiencing emotional blunting as part of major depressive disorder (MDD).

3. The aforementioned patient has a history of signs and symptoms of emotional blunting caused by drug administration, The composition according to claim 1, wherein the agent causing signs and symptoms of emotional blunting in the patient is not 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.

4. The composition according to claim 3, wherein the drug is provided for the treatment of major depressive disorder (MDD) or major depressive episode (MDE).

5. The drug is administered for the prevention or treatment of major depressive disorder (MDD) or major depressive episode (MDE), or its signs and symptoms, and the drug is not 1-[2-(2,4-dimethylphenylsulfanil)-phenyl]piperazine or a pharmaceutically acceptable salt thereof, and the emotional blunting is, 1) The result of the aforementioned major depressive disorder (MDD) or major depressive episode (MDE), 2) The result of an insufficient response to the administration of the drug, 3) The composition according to any one of claims 3 to 4, which has been reported to be caused by an inadequate response to medical treatment for major depressive disorder (MDD) or major depressive episode (MDE).

6. The composition according to any one of claims 3 to 5, wherein the drug is a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI).

7. The composition according to claim 6, wherein the drug is selected from escitalopram, fluoxetine, paroxetine, sertraline, venlafaxine, desvenlafaxine, and duloxetine.

8. The composition according to any one of claims 1 to 7, wherein the patient has a total score of 30 or more on the Oxford Depression Scale (ODQ).

9. The composition according to any one of claims 1 to 8, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrobromide, lactate, and pyroglutamate.

10. The composition according to claim 9, wherein the pharmaceutically acceptable salt is selected from hydrobromide (α), hydrobromide (β), and hydrobromide (γ).

11. The composition according to any one of claims 1 to 10, wherein 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 5 mg, 10 mg, or 20 mg of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine.

12. The composition according to any one of claims 1 to 11, wherein 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg / day, 10 mg / day, or 20 mg / day of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine.

13. The composition according to any one of claims 1 to 12, wherein 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as an oral tablet or oral drop.

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