WO2021198778A1 - 1-[2-(2,4-diméthylphénylsulfanyl)-phényl]pipérazine pour la prévention ou le traitement de l'émoussement émotionnel - Google Patents

1-[2-(2,4-diméthylphénylsulfanyl)-phényl]pipérazine pour la prévention ou le traitement de l'émoussement émotionnel Download PDF

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WO2021198778A1
WO2021198778A1 PCT/IB2021/000207 IB2021000207W WO2021198778A1 WO 2021198778 A1 WO2021198778 A1 WO 2021198778A1 IB 2021000207 W IB2021000207 W IB 2021000207W WO 2021198778 A1 WO2021198778 A1 WO 2021198778A1
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piperazine
dimethylphenylsulfanyl
phenyl
patient
pharmaceutically acceptable
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PCT/IB2021/000207
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English (en)
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Carlos Forray
Michael Cronquist CHRISTENSEN
Ioana Florea
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H. Lundbeck A/S
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Priority to AU2021246973A priority Critical patent/AU2021246973A1/en
Priority to JP2022559799A priority patent/JP2023520016A/ja
Priority to KR1020227037929A priority patent/KR20220163997A/ko
Publication of WO2021198778A1 publication Critical patent/WO2021198778A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the therapeutic use of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl] piperazine.
  • CNS disorders and conditions such as major depressive disorder (“MDD”), major depressive episodes (“MDE”), schizophrenia, or post-traumatic stress disorder (“PTSD”) are disabling and recurrent illnesses, that are highly prevalent worldwide.
  • MDD major depressive disorder
  • MDE major depressive episodes
  • PTSD post-traumatic stress disorder
  • MDD is a severe, recurrent, and disabling illness that can be treated with selective serotonin reuptake inhibitors ("SSRIs”) and serotonin-noradrenalin reuptake inhibitors ("SNRIs").
  • SSRIs serotonin reuptake inhibitors
  • SNRIs serotonin-noradrenalin reuptake inhibitors
  • Emotional blunting is a condition characterized by a restriction in emotions that clinically presents as emotional indifference and detachment, reduced responsiveness, low motivation, and apathy (Price J, Cole V, Goodwin GM., Br. J. Psychiatry, (2009), 195(3), 211-217 (incorporated herein by reference in its entirety)).
  • MDD with a prevalence of 15% worldwide, is treated with commonly used antidepressants, such as SSRIs or SNRIs as first- and second-line treatments.
  • SSRIs have for years been favored by physicians for the treatment of many central nervous system (“CNS") diseases, such as depression and anxiety, because they are effective and have favorable safety profiles compared to the previous generation of CNS drugs, i.e., the so-called tri-cyclic anti-depressants.
  • CNS central nervous system
  • Known adverse events from the treatment of MDD with antidepressants, such as SSRIs and SNRIs are changes in sleep pattern, changes in sexual functioning, headache, and weight gain.
  • a side-effect less commonly investigated in clinical trials is the blunting of emotions experienced by patients taking these medications, which also include anti-psychotic medications used in the treatment of schizophrenia.
  • Anhedonia is a state of reduced ability to experience feelings of pleasure and is a common symptom of MDD— reported in about 75% of patients (Franken et al., J. Affect. Disord.
  • Anhedonia concerns a state with lack of positive emotions, whereas emotional blunting is a state where all emotions are lacking or blunted, both positive and negative. It cannot be foreseen whether a drug, which relieves anhedonia, also relieves emotional blunting.
  • the term 'anhedonia' is primarily referred to the inability to experience pleasure (Rizvi SJ, Pizzagalli DA, Sproule BA, Kennedy SH, Neuroscience and Biobehavioral Reviews, (2016), 65, 21-35 (incorporated herein by reference in its entirety)).
  • Anhedonia is a core diagnostic feature of a major depressive episode and patients with anhedonia may endorse a diagnosis of MDD even if the 'depressed mood' criterion is not endorsed (American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders: DSM-5. Washington, D.C.: American Psychiatric Association (incorporated herein by reference in its entirety).
  • the same antidepressants may cause emotional blunting, in that they reduce the ability to experience physiological negative emotions (e.g., going to a funeral and crying; feeling sad when something bad happens) and, at the same time, they 'stabilize' positive emotions, flattening them in a range that is better than the intensity experienced during depression but is not normal.
  • patients may be improved in their anhedonia, i.e., they are no longer tormented by excessive negative emotions or unable to experience pleasure, but they are emotionally blunted, for instance in their creativity, in their ability to enjoy and engage in things, and in their reactivity to life events.
  • emotional blunting may be related to antidepressant treatment with a SSRI or SNRI.
  • emotional blunting is related to SSRI dosing, with higher doses being more likely to precipitate the syndrome (Sansone and Sansone, Psychiatry (Edgmont) (2010), 7, 14-18 (incorporated herein by reference in its entirety)), which, in some cases, may resolve with lowering the dose. In other cases, the condition does not resolve until the SSRI is discontinued.
  • Emotional blunting has been proposed to relate to serotonergic effects in the frontal lobes and/or serotonergic modulation of midbrain dopaminergic systems, which project to the prefrontal cortex.
  • GABA gamma-aminobutyric acid
  • Emotional blunting is burdensome, and negatively affects quality of life and daily functioning (Price J, Cole V, Goodwin GM., Br. J. Psychiatry, (2009), 195(3), 211-217 (incorporated herein by reference in its entirety)).
  • the blunting of emotions has real functional consequences for patients ' social, family, and work life. Some patients describe how they experience reduced love, affection, and pride towards their partner and family, reduced sympathy and empathy during social interactions, and reduced concern and interest about their responsibilities at work. A feeling of "just not caring" about things that used to matter to them was expressed by a significant proportion of the patients, and the effect was attributed to their antidepressant treatment.
  • SSRIs may show efficacy against symptoms of anhedonia during a major depressive episode (i.e., patients no longer experience excessive negative emotions or are unable to experience pleasure), but symptoms of emotional blunting may persist (e.g., patients still experience inability to enjoy and engage in usually pleasurable activities and show impaired reactivity to life events).
  • Emotional blunting and anhedonia have been implicated in disturbances of central dopaminergic, mesolimbic, and mesocortical reward circuit pathways (Pan et al., 2017 (supra); Sternat and Katzman, 2016 (supra)).
  • Patients suffering with emotional blunting may also demonstrate a persistent inability to experience positive emotions (e.g., happiness, satisfaction, or loving feelings), a markedly diminished interest or participation in significant activities, and, possibly, with feelings of detachment or estrangement from others.
  • positive emotions e.g., happiness, satisfaction, or loving feelings
  • Other related subjective experiences that may be reported by patients who feel emotionally numb can include feeling emotionally dead, shutdown, hollow and/or empty, and without any feelings.
  • a high degree of emotional dysfunction is likely to be associated with poor overall life functioning, a poorer quality of remission from depressive symptoms, and a more negative perception of the condition and could be a reason for treatment cessation (Goodwin GM, Price J, Bodinat CD, Laredo J., J. Affect. Disord. (2017), 221, 31-35 (incorporated herein by reference in its entirety)).
  • Emotional numbness is not only a reaction seen as an adverse event in medical treatment with, e.g., SSRIs or SNRIs as described above, but may also be conceptualized as part of the symptomatology of certain CNS diseases or disorders as such, e.g., as part of the development of depression or even as a biopsychological response to extreme emotional or physical trauma. Emotional numbness or blunting can thus be observed in patients who have experienced extreme emotional or physical trauma, e.g., patients diagnosed with PTSD.
  • the published pilot study reported the administration of low doses of the drug, incrementing doses gradually from one milligram twice a day up to a maximum of 200 milligrams twice a day. Based on the study results, nalmefene was observed to significantly reduce, and in some cases remit, the symptom of emotional blunting, and to facilitate the veterans' abilities to experience a range of normal human responses, including feelings of empathy, love, care, and concern for others.
  • the drug was also found to significantly improve all core symptoms of PTSD, including nightmares, intrusive thoughts, flashbacks; the inability to engage in topics dealing with combat experiences without the onset of symptoms of emotional distress or behavioral avoidance; dissociative amnesia; mistrust of others; and states of hyper arousal and reactivity associated with the traumatic events (Diagnostic Statistical Manual- 5. American Psychiatric Association, pub, 2013 (incorporated herein by reference in its entirety)).
  • SSRIs like 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 (incorporated herein by reference in its entirety));
  • SNRIs such as Cymbalta (duloxetine), Pristiq (desvenlafaxine), and Effexor XR (venlafaxine);
  • Wellbutrin differentiates itself from the other antidepressant drugs in being a dopamine and norepinephrine reuptake inhibitor. Unlike the others, Wellbutrin (bupropion) does not target serotonin transporter ("SERT") (Patel K, Allen S, Haque MN, Angelescu I, Baumeister D, Tracy DK., Ther. Adv. Psychopharmacol. (2016), 6(2), 99-144 (incorporated herein by reference in its entirety)). This may thus suggest that inhibition of serotonin may be one of the prime causes of emotional blunting for antidepressants, such as SSRIs or SNRIs.
  • SERT serotonin transporter
  • vortioxetine is able to provide relief in about half of the patients experiencing emotional blunting and significantly reduce symptoms of emotional blunting in all patients participating in the study, an effect observed already after 1 week of treatment and increasing in size over the next 7 weeks of treatment.
  • This effect should be expected regardless of whether the emotional blunting is a direct result of the medical treatment with antidepressant or whether the medical treatment with antidepressants revealed an underlying symptom to be treated.
  • Similar effects can be expected for the treatment of emotional blunting as part of the negative symptoms in, e.g., schizophrenia or psychosis or in patients who experience a worsening of negative symptoms due to treatment with medicaments for the treatment of schizophrenia or psychosis, such as antipsychotics.
  • Antipsychotics also called neuroleptics
  • neuroleptics are a class of compounds with a high affinity for several subtypes of dopamine receptors. The chemical structure of the various antipsychotics allows them to bind to dopamine receptors without triggering the postsynaptic response that the binding of dopamine normally would. Because of their ability to block dopamine receptors without causing the opening of ion channels and setting off an action potential, neuroleptics can be administered to schizophrenic patients to help reduce excess levels of dopamine, and to thus help alleviate the positive symptoms of the disorder.
  • the traditional typical and atypical antipsychotics demonstrate clinical efficacy in treating positive symptoms, such as hallucinations and delusions, while are largely ineffective and may even worsen negative symptoms, such as emotional blunted affect and social withdrawal, as well as cognitive function.
  • positive symptoms such as hallucinations and delusions
  • negative symptoms such as emotional blunted affect and social withdrawal, as well as cognitive function.
  • the inability to treat these latter symptoms may contribute to social function impairment associated with schizophrenia.
  • the dysfunction of multiple neurotransmitter systems in schizophrenia suggests that drugs selectively targeting one neurotransmission 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 (incorporated herein by reference in its entirety).
  • WO 2003/029232 (incorporated herein by reference in its entirety) and WO 2007/144005 (incorporated herein by reference in its entirety) disclose the compound l-[2- (2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine and pharmaceutically acceptable salts thereof.
  • Vortioxetine (which is l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine) is a multimodal antidepressant that works through modulation of receptor activity and serotonin transporter inhibition. As of July 1, 2020, vortioxetine has been approved for the treatment of major depression globally in more than 80 countries, including by the FDA in September 2013 and European Commission on December 18, 2013.
  • vortioxetine was efficacious, safe, and well tolerated in adults and the elderly with MDD, in short-term treatment and long-term maintenance treatment.
  • the approved therapeutic dose range for vortioxetine in adults is 5-20 mg/day.
  • Vortioxetine is a multi-modal antidepressant sharing some common features with SSRIs and SNRIs. However, since vortioxetine is a multi-modal antidepressant which has also shown a different pattern of effects and side effects than SSRI and SNRIs, a clinical trial under the name study name COMPLETE, study number 17797A (EudraCT No. 2017-004829-33 (incorporated herein by reference in its entirety)), sponsored by H. Lundbeck A/S, was set up to assess the effect of vortioxetine on emotional blunting. In clinicaltrial.gov study No.
  • NCT 03835715 (incorporated herein by reference in its entirety), the Brief Summary summarizes the study's aim as: "The study will evaluate effectiveness of flexible dose vortioxetine on Emotional Functioning in patients with Major Depressive Disorder with an inadequate response to SSRI/SNRI".
  • the EudraCT trial register cites the same purpose in the Full Title of the Trial.
  • WO 2009/062517 (supra) at example 5 demonstrates that l-[2-(2,4-dimethylphenyl--sulfanyl)-phenyl]piperazine compounds give rise to an increase in extra-cellular levels of acetylcholine in the prefrontal cortex and the ventral hippocampus in rats, and example 6 demonstrates that they improved contextual memory in rats.
  • no data has been reported on the effects of vortioxetine on emotional blunting.
  • the invention relates to l-[2-(2,4-dimethylphenyl-sulfanyl)-phenyl]piperazine, the structure of which is and pharmaceutically acceptable salts thereof, for use in the treatment, prevention, or reduction of emotional blunting.
  • Oral dosage forms, and in particular tablets, are often preferred by the patients and the medical practitioner due to the ease of administration and the consequent better compliance.
  • the active ingredients are crystalline.
  • the invention relates to compounds that are crystalline.
  • WO 2007/144005 discloses several pharmaceutically acceptable salts and solvates of l-[2-(2,4-dimethylphenyl-sulfanyl)- phenyl]piperazine.
  • a preferred salt of l-[2-(2,4-dimethylphenyl-sulfanyl)-phenyl]piperazine is the hydrobromide salt; l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine HBr.
  • WO 2007/144005 further discloses X-ray powder diffraction ("XRPD") reflections of further salts used in the present invention. The table below summarizes the major XRPD reflections of some compounds used in the present invention.
  • Selected X-ray peak positions (02°); all values ⁇ 0.2°, preferably ⁇ 0.1°.
  • the crystalline compounds used herein may exist in more than one form, i.e., they may exist in polymorphic forms. Polymorphic forms exist if a compound can crystallize in more than one form. The present invention is intended to encompass all such polymorphic forms, either as pure compounds or as mixtures thereof.
  • the present invention uses compounds in a purified form.
  • purified form is intended to indicate that the compound is essentially free of other compounds or other forms of the same compound.
  • vortioxetine The mechanism of action of vortioxetine is thought to be related to its direct modulation of serotonergic receptor activity and inhibition of the serotonin (5-HT) transporter (SERT).
  • 5-HT serotonin
  • Nonclinical data indicate that vortioxetine is a 5-HT3, 5-HT7, and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, and 5-HT1A receptor agonist and inhibitor of the SERT, leading to modulation of neurotransmission in several systems.
  • This multimodal activity is considered to be responsible for the antidepressant and anxiolytic-like effects and the improvement of cognitive function, learning, and memory observed with vortioxetine in animal studies.
  • the present invention relates to prevention, treatment or reduction of signs and symptoms of emotional blunting in patients.
  • Such patients may or may not be diagnosed with one or more CNS diseases or conditions and such patients may or may not have a history of signs and symptoms of emotional blunting resulting from an administration of a medicament.
  • a CNS disease or disorder is selected from the group of psychiatric disorders, such as psychosis, schizophrenia, schizoaffective disorder, schizophreniform disorder, catatonia, delusional disorder; mood disorders, such as bipolar disorder, cyclothymic disorder, major depression disorder, dysthymia, premenstrual dysphoric disorder, and substance use disorders.
  • said one or more CNS diseases or conditions is selected from the group consisting of PTSD, depression, including MDD and major depressive episodes ("MDE"), cognitive impairment, schizophrenia, psychosis, Parkinson's disease, autism, vascular dementia, and multiple system atrophy and wherein said patients experience an inadequate response to said treatment, resulting in reporting or diagnosis or diagnosis of adverse events, symptoms or signs of emotional blunting as a result of such treatment.
  • the invention also relates to prevention or treatment of emotional blunting in patients receiving treatment for one or more CNS diseases or conditions, wherein said emotional blunting is a result of inadequate response to said treatment for one or more CNS diseases or conditions.
  • the invention also relates to prevention or treatment of emotional blunting in patients receiving medical treatment for one or more CNS diseases or conditions, wherein said emotional blunting is a result of said medical treatment for one or more CNS diseases or conditions.
  • the invention further relates to prevention, treatment, or reduction of signs and symptoms of emotional blunting in patients receiving treatment for one or more CNS diseases or conditions; PTSD, depression, including MDD and MDE, cognitive impairment, schizophrenia, psychosis, Parkinson's disease, autism, vascular dementia, and multiple system atrophy and wherein said patients experience an inadequate response to said treatment, resulting in reporting or diagnosis of adverse events, symptoms or signs of emotional blunting as a result of such treatment.
  • the invention further relates to prevention or treatment or reduction of signs and symptoms of emotional blunting in patients who were treated for one or more diseases or conditions; PTSD, depression, cognitive impairment, schizophrenia, psychosis, Parkinson's disease, autism, vascular dementia, and multiple system atrophy and wherein said patients experienced an inadequate response associated with said treatment for one or more diseases or conditions, resulting in reporting or diagnosis of adverse events, symptoms or signs of emotional blunting as a result of such treatment.
  • the invention further relates to prevention or treatment or reduction of signs and symptoms of emotional blunting in patients who were diagnosed 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 and wherein said patients experienced an inadequate response associated with said treatment for one or more diseases or conditions, resulting in reporting or diagnosis of adverse events, symptoms or signs of emotional blunting as a result of such treatment.
  • the invention further relates to prevention of signs and symptoms of emotional blunting in patients who were diagnosed 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 and wherein said patients experienced an inadequate response associated with said treatment for one or more diseases or conditions, resulting in reporting or diagnosis of adverse events, symptoms or signs of emotional blunting as a result of such treatment.
  • the invention further relates to treatment or reduction of signs and symptoms of emotional blunting in patients who were diagnosed 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 and wherein said patients experienced an inadequate response associated with said treatment for one or more diseases or conditions, resulting in reporting or diagnosis of adverse events, symptoms or signs of emotional blunting as a result of such treatment.
  • the invention further relates to prevention or treatment or reduction of signs and symptoms of emotional blunting in patients who were diagnosed 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 and wherein said patients experienced an inadequate response associated with said treatment for one or more diseases or conditions, resulting in reporting or diagnosis of adverse events, symptoms or signs of emotional blunting as a result of such treatment.
  • the invention further relates to prevention of signs and symptoms of emotional blunting in patients who were diagnosed 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 and wherein said patients experienced an inadequate response associated with said treatment for one or more diseases or conditions, resulting in reporting or diagnosis of adverse events, symptoms or signs of emotional blunting as a result of such treatment.
  • the invention further relates to treatment or reduction of signs and symptoms of emotional blunting in patients who were diagnosed 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 and wherein said patients experienced an inadequate response associated with said treatment for one or more diseases or conditions, resulting in reporting or diagnosis of adverse events, symptoms or signs of emotional blunting as a result of such treatment.
  • the invention further relates to prevention or treatment or reduction of signs and symptoms of emotional blunting in patients who are treated for a CNS disease selected from the group of psychiatric disorders, such as schizophrenia, psychosis, schizoaffective disorder, schizophreniform disorder, catatonia, delusional disorder; mood disorders, such as bipolar disorder, cyclothymic disorder, major depression, dysthymia, premenstrual dysphoric disorder, and substance use disorders.
  • psychiatric disorders such as schizophrenia, psychosis, schizoaffective disorder, schizophreniform disorder, catatonia, delusional disorder
  • mood disorders such as bipolar disorder, cyclothymic disorder, major depression, dysthymia, premenstrual dysphoric disorder, and substance use disorders.
  • the invention further relates to prevention or treatment or reduction of signs and symptoms of emotional blunting in patients who are treated for a CNS disease that is a psychiatric disorder, such as psychosis, schizophrenia, schizoaffective disorder, schizophreniform disorder, catatonia, and delusional disorder.
  • a CNS disease that is a psychiatric disorder, such as psychosis, schizophrenia, schizoaffective disorder, schizophreniform disorder, catatonia, and delusional disorder.
  • the invention further relates to prevention or treatment or reduction of signs and symptoms of emotional blunting in patients who are treated for a CNS disease that is a mood disorder, such as bipolar disorder, cyclothymic disorder, major depression, dysthymia, and premenstrual dysphoric disorder.
  • a mood disorder such as bipolar disorder, cyclothymic disorder, major depression, dysthymia, and premenstrual dysphoric disorder.
  • the invention further relates to prevention or treatment or reduction of signs and symptoms of emotional blunting in patients who are treated for a CNS disease which is a substance use disorder or associated with a substance use disorder.
  • Figure 1 provides a schematic overview of the study described in Assay l-XI; results are disclosed in Examples 1-12.
  • Figure 2 shows an overview of the Oxford Depression Questionnaire ("ODQ") ( ⁇ Oxford University Innovation Limited, 2011) total score (FAS, MMRM) from baseline, over week 1, 4, and the end of the study at week 8, and reflects the numbers as described in Table 3.
  • ODQ Oxford Depression Questionnaire
  • Figure 3 shows the base line scores of ODQ ( ⁇ Oxford University Innovation Limited, 2011) total scores, showing that the scores are normally distributed.
  • Figure 4 is a graph visualizing the base line scores of MEI total scores, showing that the scores are normally distributed.
  • Figure 5 summarizes the clinical assessment of emotional blunting and partial correlation and mediation analyses
  • Figure 6 shows that improvements in motivation and energy assessed using the MEI were substantial and significant already from week 4 and across all subdomains: cognitive and mental energy, social motivation, and physical energy; *** means p ⁇ 0.0001.
  • Figure 7 depicts that the mediation analysis further shows that 63.4% of the change in SDS total score explained by change in ODQ ( ⁇ Oxford University Innovation Limited, 2011) total score was a direct effect of improvement in ODQ ( ⁇ Oxford University Innovation Limited, 2011) after switching to vortioxetine that could not be explained by improved depressive symptoms (MADRS), which accounted for 36.6% of the effect on SDS total score.
  • MADRS improved depressive symptoms
  • the present inventors have found that l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine, exerting a combination of SERT inhibition, 5-HT3 antagonism, and 5-HT1A agonism, is useful in the prevention of treatment of emotional blunting in patients with CNS disorders and/or in patients receiving medicament for the treatment of one or more CNS disorders.
  • the invention provides a method for the prevention or treatment of or reducing emotional blunting related to one or more CNS diseases or conditions, the method comprising the administration of a therapeutically effective amount of l-[2-(2,4- dimethylphenylsulfanyl)phenyl]-piperazine or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • the invention provides a method for the prevention or treatment of or reducing emotional blunting related to one or more CNS diseases or conditions, the method comprising the administration of a therapeutically effective amount of l-[2-(2,4- dimethylphenylsulfanyl)phenyl]-piperazine or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein said administration of a therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)phenyl]-piperazine or a pharmaceutically acceptable salt thereof is either provided as a monotherapy or concomitant with other medicaments for the prevention or treatment of one or more CNS diseases or disorders.
  • the present invention further relates to a method of preventing or treating emotional blunting or signs and symptoms thereof in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the present invention further relates to a method of preventing or treating emotional blunting in a patient wherein said patient experiences emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting resulting from an inadequate response to a medicament, the method comprising administering to a patient in need thereof a therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the present invention also relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use in preventing or treating emotional blunting in a patient. It further relates to l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof for use in preventing or treating emotional blunting in a patient wherein said patient experiences emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting resulting from an administration of a medicament, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2- (2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the emotional blunting as seen in patients, which are proposed to receive l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof, administered either as monotherapy or concomitant with other medicaments for the treatment of one or more CNS diseases or disorders, may be seen in connection with administration of an adequate dose of a medicament for the treatment of one or more CNS diseases or disorders, wherein said adequate dose of said medicament is a dose as described in said medicament's label.
  • said medicament for treatment of one or more CNS disease or disorders is an antidepressant, anti-psychotic, or a medicament for the treatment of psychosis or schizophrenia.
  • monotherapy of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof necessitates that a previously administered antidepressant, such as SSRIs or SNRIs, are discontinued before said monotherapy is begun.
  • a previously administered antidepressant such as SSRIs or SNRIs
  • concomitant administration of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine is with another medicament for the treatment of one or more CNS disease or disorder is an administration of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine at the same time (or alongside) the administration of another medicament.
  • an “another medicament” can be a medicament reducing the dopaminergic transmission or any other medicament used in the treatment of CNS disease or disorder.
  • such an "another medicament” can be an antipsychotic.
  • Vortioxetine is a multi-modal antidepressant sharing some common features with SSRIs and SNRIs. However, since vortioxetine is a multi-modal antidepressant which has also shown a different pattern of effects and side effects than SSRI and SNRIs, a clinical trial under the name study name COMPLETE, study number 17797A (EudraCT No. 2017-004829-33 (supra)) sponsored by H. Lundbeck A/S was set up to assess the effect of vortioxetine on emotional blunting. In clinicaltrial.gov study No.
  • NCT 03835715 (supra), the Brief Summary summarizes the study's aim as: "The study will evaluate effectiveness of flexible dose vortioxetine on Emotional Functioning in patients with Major Depressive Disorder with an inadequate response to SSRI/SNRI”.
  • the EudraCT trial register cites the same purpose in the Full Title of the Trial.
  • results of this study were used to evaluate the effectiveness of vortioxetine 10-20 mg/day for preventing and/or treating emotional blunting in patients with MDD who are known to experience inadequate response to an SSRI/SNRI for a current depressive episode, and who have a desire to switch to an alternative antidepressant, wherein such inadequate response is determined in the form of reporting or diagnosis, and may include all symptoms of depression, including symptoms or signs of emotional blunting.
  • negative symptoms have repeatedly emerged as a separate factor, independent of positive symptoms, disorganization, and affective symptoms, including depression and anxiety. Additional research focusing on the latent structure of negative symptoms themselves suggests that this symptom domain is not unidimensional.
  • the most reliable factors to emerge within negative symptoms include diminished expression (typically involving symptoms of reduced facial and vocal expressivity and reduced verbal output) and a factor tapping anhedonia and asociality (composed of symptoms of anhedonia, diminished interest, and decreased social engagement) (Blanchard JJ, Cohen AS. The structure of negative symptoms within schizophrenia: implications for assessment. Schizophr Bull. 2006;32: 238-245 (incorporated herein by reference in its entirety)).
  • Blunted affect can be found in several disorders other than schizophrenia, including, e.g., Parkinson's disease, depression, autism, vascular dementia, and multiple system atrophy.
  • antipsychotic medications complicate the assessment of blunted affect, as they can induce this symptom (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.
  • a l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine compound as used in this invention is the hydrobromic acid salt.
  • a l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine compound as used in this invention is the hydrobromic acid salt, e.g., in the beta form.
  • a l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine compound as used in this invention is the hydrobromic acid salt, and suitable tablets may be composed of the following ingredients:
  • the tablets may be composed of the following ingredients:
  • Tablets with different amounts of active compound may be obtained by choosing the right amount of the l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine compound in combination with a tablet of an appropriate size.
  • Preferred concentrations of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine HBr salt are about 5 mg, about 10 mg, or about 20 mg per tablet.
  • Preferred concentrations of l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine HBr salt are about 5 mg per tablet.
  • Preferred concentrations of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine HBr salt are about 10 mg per tablet.
  • Preferred concentrations of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine HBr salt are about 20 mg per tablet.
  • Preferred administration frequency for tablets ether comprising about 5 mg, about 10 mg, or about 20 mg l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or any pharmaceutically acceptable salt thereof is once daily. Patients starting in about 5 mg daily may increase the concentration to about 10 mg per day or about 20 mg per day.
  • Therapeutically effective amounts of l-[2- (2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof may for example be about 5 mg, about lOmg, or about 20mg l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine per day.
  • the invention relates to a method of preventing or treating emotional blunting or signs and symptoms thereof in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the invention relates to a method of preventing or treating emotional blunting or signs and symptoms thereof in a patient, wherein said patient experiences signs and symptoms of emotional blunting, the method comprising administering to a patient in need thereof a therapeutically effective amount of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • said method of preventing or treating emotional blunting or signs and symptoms thereof in a patient is a method wherein said patient experiences signs and symptoms of emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • said method of preventing or treating emotional blunting or signs and symptoms thereof in a patient is a method wherein said patient experiences emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting in connection with the administration of a medicament, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • said method of preventing or treating emotional blunting or signs and symptoms thereof in a patient is a method wherein said patient experiences emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting resulting from an administration of a medicament, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • said method of preventing or treating emotional blunting or signs and symptoms thereof in a patient is a method wherein said patient experiences emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting resulting from an administration of a medicament at an adequate dose, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2- (2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • said method of preventing or treating emotional blunting or signs and symptoms thereof in a patient is a method wherein said patient experiences emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting resulting from an inadequate response to a medical treatment, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • said method of preventing or treating emotional blunting or signs and symptoms thereof in a patient is a method wherein said patient experiences emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting resulting from an inadequate response to a medical treatment of a CNS disease or disorder, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • said method of preventing or treating emotional blunting or signs and symptoms thereof in a patient wherein said patient has a history of showing signs and symptoms of emotional blunting in connection with a CNS disease or disorder or a medical treatment of one or more CNS disease or disorder, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof
  • said method comprising the steps of: i) evaluation of said patient by a practicing clinician or physician, wherein said evaluation includes
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use in preventing or treating emotional blunting or signs and symptoms thereof in a patient.
  • the invention relates to said use for preventing or treating emotional blunting or signs and symptoms thereof in a patient, wherein said patient experiences signs and symptoms of emotional blunting.
  • the invention relates to said use for preventing or treating emotional blunting or signs and symptoms thereof in a patient, wherein said patient experiences signs and symptoms of emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the invention relates to said use for preventing or treating emotional blunting or signs and symptoms thereof in a patient, wherein said patient experiences emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting in connection with the administration of a medicament, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the invention relates to said use for preventing or treating emotional blunting in a patient wherein said patient experiences emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting resulting from an administration of a medicament, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the invention relates to said use for preventing or treating emotional blunting in a patient wherein said patient experiences emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting resulting from an administration of a medicament or treating one or more CNS disease or disorder, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the invention relates to said use for preventing or treating emotional blunting in a patient wherein said patient has experienced emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting resulting from an administration of a medicament at an adequate dose, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the invention relates to said use for preventing or treating emotional blunting in a patient wherein said patient has a history of showing signs and symptoms of emotional blunting in connection with a CNS disease or disorder or a medical treatment of one or more CNS disease or disorder, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof, the method comprising the steps of: i) evaluation of said patient by a practicing clinician or of physician, wherein said evaluation includes 1) an evaluation of said patient's history of signs and symptoms of emotional blunting;
  • an adequate dose of said medicament is a dose as described in said medicament's label.
  • a method or l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use in preventing or treating emotional blunting according to this invention refers to a medicament for the treatment of one or more CNS disease or disorder an adequate dose thereof, wherein adequate dose of said medicament, which is not-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof, is a dose described in said medicament's label and selected from any one of doses described for efficient treatment in the label of said medicament.
  • a method or for preventing or treating emotional blunting or signs and symptoms thereof as described herein comprises the steps of:
  • a method or for preventing or treating emotional blunting or signs and symptoms thereof as described herein comprises the steps of: a. discontinuation of said medicament for the treatment of a CNS disease or disorder; and b. administering to a patient in need thereof a therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • a method or for preventing or treating emotional blunting or signs and symptoms thereof as described herein comprises the steps of: a. maintaining administration of said medicament for the treatment of a CNS disease or disorder; and b. administering to a patient in need thereof a therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the method or l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof for use in prevention or treatment of emotional blunting is for preventing emotional blunting in a patient.
  • the method or l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof for use in prevention or treatment of emotional blunting is for treating emotional blunting in a patient.
  • said emotional blunting is associated with a CNS disease or disorder.
  • said emotional blunting is associated with an underlying CNS disease or disorder.
  • said medicament is for treatment of one or more CNS diseases or disorder, or signs and symptoms thereof.
  • said emotional blunting is reported by said patient.
  • said emotional blunting is diagnosed by a practicing clinician or physician.
  • said emotional blunting is reported by said patient, as being caused by of an inadequate response of a medical treatment of a CNS disease or disorder.
  • said emotional blunting is diagnosed by a practicing clinician or physician by evaluating the patient, wherein said evaluation comprises the steps of: a) explaining to said patient that: "Emotional effects vary, but may include, for example, feeling emotionally “numbed” or “blunted” in some way; lacking positive emotions or negative emotions; feeling detached from the world around you; or “just not caring” about things that you used to care about”; b) asking the question: "Have you experienced such emotional effects during the last 6 weeks?"; c) evaluating the response to question b) and concluding if symptoms or signs of emotional blunting is present in said patient; and, optionally, d) if the evaluation of step c) is that said patient experiences emotional blunting, said practicing clinician or physician decides to apply the method or use for treating emotional blunting as described in aspects and embodiments herein.
  • step c) of said practicing clinician or physician's evaluation leads to the conclusion of the presence of emotional blunting, if said patient's answer to the question asked in step b) is "yes.”
  • said emotional blunting is diagnosed by a practicing clinician or physician by evaluating the patient, wherein said evaluation comprises the steps of: a) explaining to said patient that: "Emotional effects vary, but may include, for example, feeling emotionally “numbed” or “blunted” in some way; lacking positive emotions or negative emotions; feeling detached from the world around you; or “just not caring” about things that you used to care about”; b) asking the question: "Have you experienced such emotional effects during the last 6 weeks?"; c) evaluating the response to question b) and, if question b) was answered with a "yes,” concluding that symptoms or signs of emotional blunting is present in said patient.
  • said step a)-c) of said practicing clinician or physician's evaluation may be supplemented or replaced by an evaluation according to or equivalent to the ODQ total score, wherein said ODQ total score is calculated based on the ODQ guidelines; and, optionally, d) if the evaluation of step c) is that said patient experiences emotional blunting, said practicing clinician or physician decides to apply the method or use for treating emotional blunting as described in aspects and embodiments herein.
  • the ODQ was developed to specifically evaluate symptoms of emotional blunting in patients with MDD (Price et al., 2012 (supra)). Results of this analysis of data from the COMPLETE study demonstrate that the ODQ ( ⁇ Oxford University Innovation Limited, 2011), both the part of the questionnaire that covers the two first sections and the full questionnaire with all 3 sections, captures aspects and symptoms of MDD that are not adequately covered by other scales commonly used to assess depression severity.
  • vortioxetine as used herein can be used interchangeably with the term “1- [2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine" or "Lu AA21004,” it is known as the active ingredient in Brintellix ® or Trintellix ® .
  • the phrase "l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof" as used herein discloses all pharmaceutically acceptable salts of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine and the phrase “l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof” specifically includes "vortioxetine," "l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine HBr," or "Lu AA21004".
  • emotional blunting can be used interchangeably with the term “emotional numbness” and refers to a person's subjective experience of the inability to feel emotions, and is accompanied by a lack of care and concern for self and others.
  • the terms “numbness” or “numbing” or other versions of the word and “blunting” or “blunted” and other versions of the word can be used interchangeably.
  • “Emotional numbness” or “emotional blunting” as used herein is distinguished from depression.
  • the emotional blunting is a direct result of the medical treatment of CNS diseases or conditions, such as, e.g., antidepressants or anti-psychotics.
  • the emotional blunting is a direct result of the medical treatment of CNS diseases or conditions, such as, e.g., antidepressants. In some aspects, the emotional blunting is a direct result of the medical treatment of CNS diseases or conditions, such as SSRI or SNRIs. In some aspects, the emotional blunting described herein may be an underlying symptom of a CNS disease or condition. In some aspects, the emotional blunting described herein may be an underlying symptom of a CNS disease or condition revealed by the treatment with medicaments for related or unrelated CNS diseases or conditions, such as, e.g., antidepressant or anti-psychotics.
  • the term "underlying" in this context means that once the antidepressants alleviate depression, the underlying symptoms of emotional blunting may be revealed rather than caused.
  • Emotional blunting thus denotes herein an absence of feelings (including those of depression and sadness).
  • a numbed or blunted individual lacks feeling of regard, concern, caring or empathy for himself/herself and others.
  • Common terms which traumatized persons use to describe this numb state of mind include shutdown, numb, ice cold, hollow, dead, and empty and no feelings, care, or concern for anyone or anything.
  • Family members commonly regard relations who are numb as being cold, heartless, and emotionally unresponsive.
  • a profoundly numb individual may have a wooden facial expression rather than one that is depressed.
  • the emotionally numbed individual may appear to be angry or sad to others yet respond with bewilderment or denial when questioned about his/her look of anger or sadness.
  • CNS disease or condition can be used interchangeably with the term "CNS disease or disorder” and is meant to describe CNS disease, which is a broad category of conditions in which the brain does not function as it should, limiting health and the ability to function.
  • the condition may be an inherited metabolic disorder; the result of damage from an infection, a degenerative condition, stroke, a brain tumor, or other problem; or arise 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 nervous system circuits that orchestrate functions as varied as memory formation (in Alzheimer's disease) or voluntary motion (in movement disorders). While most conditions in this group cannot be completely cured, symptoms of central nervous system diseases can often be managed through a range of therapies, from medical to surgical treatment.
  • CNS disease or condition or “CNS disease or disorder” is meant to include disorders or conditions such as psychiatric disorders, such as schizophrenia, schizoaffective disorder, schizophreniform disorder, catatonia, delusional disorder; mood disorders, such as bipolar disorder, cyclothymic disorder, major depression, dysthymia, premenstrual dysphoric disorder; and substance use disorders.
  • psychiatric disorders such as schizophrenia, schizoaffective disorder, schizophreniform disorder, catatonia, delusional disorder
  • mood disorders such as bipolar disorder, cyclothymic disorder, major depression, dysthymia, premenstrual dysphoric disorder
  • substance use disorders such as bipolar disorder, cyclothymic disorder, major depression, dysthymia, premenstrual dysphoric disorder.
  • CNS diseases or conditions may be used interchangeably with the term “CNS diseases or disorders” and include psychiatric and neurological disorders.
  • CNS diseases or conditions include psychiatric and neurological disorders, such as depression, e.g., MDD or MDE, PTSD, schizophrenia, Parkinson's disease, autism, vascular dementia, and multiple system atrophy.
  • CNS diseases or conditions comprise any one or more of the following: MDD or MDE, PTSD, schizophrenia, Parkinson's disease, autism, vascular dementia, and multiple system atrophy.
  • Psychosis is part of schizophrenia, and it can be part of other disorders as well.
  • Psychosis is a concept that describes specific symptoms. Schizophrenia is a mental illness that has psychotic features. Psychotic symptoms include hallucination, delusion, confusion, inability to think clearly, rapid and/or racing thoughts, confused speech, disorganized behavior, and catatonic behavior, however not all of these symptoms need be present.
  • schizophrenia psychosis is the first criteria that must be met for a diagnosis of schizophrenia. Without psychosis, there is no schizophrenia, however psychosis can present alone, without schizophrenia.
  • disorders which may involve "psychosis” can be other psychotic disorders (schizophrenia, schizoaffective disorder, schizophreniform disorder, catatonia, delusional disorder), mood disorders (bipolar disorder, cyclothymic disorder, major depression, dysthymia, premenstrual dysphoric disorder), and substance use disorders.
  • psychotic disorders schizophrenia, schizoaffective disorder, schizophreniform disorder, catatonia, delusional disorder
  • mood disorders bipolar disorder, cyclothymic disorder, major depression, dysthymia, premenstrual dysphoric disorder
  • substance use disorders can be other psychotic disorders (schizophrenia, schizoaffective disorder, schizophreniform disorder, catatonia, delusional disorder), mood disorders (bipolar disorder, cyclothymic disorder, major depression, dysthymia, premenstrual dysphoric disorder), and substance use disorders.
  • antipsychotics or “antipsychotic drugs” or “neuroleptics” as used herein may be used interchangeably and may be included in the term “medicament for the treatment of schizophrenia” or “medical treatment of schizophrenia” or similar phrases used herein, because schizophrenic patients often are treated for the psychosis with such drugs.
  • the term “medicament for the treatment of schizophrenia” or “medical treatment of schizophrenia” or similar phrases used herein may thus include “atypical antipsychotics” and/or "typical antipsychotics.”
  • "atypical antipsychotics” may, for example, be selected from the group comprising aripiprazole, iloperidone, ziprasidone, lurasidone, risperidone, brexpriprazole, asenapine, quetiapine, cariprazine, and olanzapine.
  • Clozapine is a special atypical antipsychotic, which is usually only prescribed when other antiphycotics fail to relief symptoms, or when the schizophrenic patient suffers from suicidal thoughts.
  • "typical antipsychotics” may for example be selected from the group comprising haloperidol, loxapine, thiothixene, fluphenazine, chlorpromazine, perphenazine, and trifluoperazine.
  • antipsychotics are grouped in the class N05A, wherein the subdivision is performed mainly based on chemical structure; sub class A is phenothiazines with aliphatic side- chain, including N05AA01 chlorpromazine, N05AA02 levomepromazine, N05AA03 promazine, N05AA04 acepromazine, N05AA05 triflupromazine, N05AA06 cyamemazine, and N05AA07 chlorproethazine; sub class B is phenothiazines with piperazine structure, including N05AB01 dixyrazine, N05AB02 fluphenazine, N05AB03 perphenazine,
  • the ATC/DDD index of the WHO other antiphycotics are grouped in the class N05AX, which included the code N05AX07 for prothipendyl, N05AX08 for risperidone, N05AX10, mosapramine, N05AX11 zotepine, N05AX12 aripripazole, N05AX13 paliperidone, N05AX14 iloperioden, N05AX15 ccariprazine, N05AX16 brexpriprazole, and N05AX17 pimavanserin.
  • "emotional blunting" is seen in patients with signs and/or symptoms of one or more CNS diseases or conditions, in patients diagnosed with one or more CNS diseases and/or in patients who receive medical treatment for one or more CNS diseases or condition.
  • blunting when blunting is profound, the patient may experience no feeling and the person may take on an expressionless and lifeless appearance.
  • individuals with numbed emotions are generally unresponsive to the environment and they are socially withdrawn. Unresponsiveness to the environment may be a composite disturbance representing a diminished level of mental alertness and awareness and a loss of interest in the outside world. Individuals with blunted emotions may not experience an empathic bond or a sense of relatedness to others. In social situations they tend to feel alienated and apart.
  • emotional blunting is associated with numbness and/or paresthesia of the body and feelings of heaviness or paralysis.
  • severe emotional blunting may be accompanied by a profound impairment of concentration and memory with an amnesia for events occurring during the numb state.
  • information processing of any kind may be severely impaired.
  • emotional blunting When emotional blunting is severe and prolonged, it is usually accompanied by a lack of motivation, interest, or pleasure in life activities.
  • blunted individuals may thus be emotionally, mentally, psychologically, and socially impaired.
  • Emotional numbing is generally appreciated as a subjective complaint.
  • emotional numbness or blunting can vary along three parameters: duration, severity, and social context. In some aspects, such numbness or blunting can be experienced for minutes, hours, days, months, or years on a continuous or intermittent basis.
  • a person who has severe or profound emotional numbing or blunting does not have any feelings at all.
  • emotions associated with high levels of physiological arousal may be experienced, e.g., rage, fear, and vulnerability.
  • tender affectionate feelings are not felt.
  • some individuals with severely blunted emotions may be able to experience love and concern towards a specific individual(s). This may be a child, trusted spouse, or fellow survivor of a traumatic episode.
  • emotional numbing may be accompanied by a physical experience of heaviness or paralysis of the body, pins and needles, tingling or numbness of parts of the body, feelings of unreality, alienation, and detachment from others.
  • cognitive disturbances can include mental confusion, amnesia, impaired concentration, indecisiveness, inability to plan future actions, and a paralysis of will.
  • cognitive disturbances may occur independent of the level of physiological arousal or distress; forgetfulness, disorientation, or confusion can occur without any apparent preceding increase in stress or anxiety.
  • patients are not able to make the distinction between the mental states of numbness and depression.
  • impaired cognitions including an absence of self-awareness, may interfere with an individual's ability to distinguish between numbness and depression.
  • individuals may frequently shift between states of depression and numbness or blunting, which makes it difficult for them to distinguish their subjective experiences.
  • numbness and depression also share certain symptoms, including impaired concentration and memory and lack of interest and pleasure in life activities.
  • the mental state of emotional numbness or blunting is a disabling condition for the patient and his or her family members.
  • numbness or blunting interferes with a person's ability to enjoy and participate in life activities (work, intimacy, sex, etc.) and with the individual's ability to respond with genuine affection, interest or concern about anybody or anything, which can oftentimes lead to marital and family discord.
  • individuals with emotional numbing may seek out sensation and risk taking activities, such as skydiving, racing cars, gambling, drug abuse, self-inflicted pain, etc., in an effort to escape the deadening effect of numbness.
  • these activities can assume a compelling addictive drive accompanied by intense feelings of craving.
  • the presence of emotional numbing or blunting can be evaluated clinically with, e.g., the tests and assessment methods described herein.
  • a neuropsychological test for evaluating cognitive functioning may be the Digit-Symbol Substitution Test ("DSST").
  • the presence of emotional blunting can be evaluated clinically as part of the psychiatric diagnosis of PTSD.
  • patient-reported signs and/or symptoms of emotional blunting may be collected at least an answer from said patient to the question: Have you experienced such emotional effects during the last 6 weeks?".
  • patient-reported signs and/or symptoms of emotional blunting may be collected at least an answer from said patient to the question: "Have you experienced such emotional effects during the last 6 weeks?", wherein said patient has been informed about the general emotional effects of emotional blunting.
  • patient-reported signs and/or symptoms of emotional blunting may be collected at least an answer from said patient to the question: "Have you experienced such emotional effects during the last 6 weeks?", wherein said patient has been informed about the general emotional effects of emotional blunting, wherein said general emotional effects may be described as: "Emotional effects vary, but may include, for example, feeling emotionally “numbed” or “blunted” in some way; lacking positive emotions or negative emotions; feeling detached from the world around you; or “just not caring” about things that you used to care about.
  • Oxford Depression Questionnaire or "ODQ” as used herein refers to the Oxford Depression Questionnaire ("ODQ”).
  • ODQ is a patient-centred, self-report measure of emotional symptoms present in patients treated with antidepressants, which was formerly called the Oxford Questionnaire on the Emotional Side-Effects of Antidepressants ("OQuESA” or “OQESA”).
  • OQuESA Emotional Side-Effects of Antidepressants
  • OQuESA Emotional Side-Effects of Antidepressants
  • the ODQ which is used and referred to in the present invention, is the Oxford Depression Questionnaire (ODQ) ( ⁇ Oxford University Innovation Limited, 2011), and is subject to a license to Oxford University Innovation Limited.
  • ODQ is a 26-item patient self-complete measure, spread over 3 sections and covering 4 dimensions (derived from qualitative research) of not caring ("NC"), emotional detachment ("ED"), positive reduction ("PR”), and general reduction (“GR”). If required, an additional dimension, Antidepressant as cause (“AC”), can also be scored.
  • NC not caring
  • ED emotional detachment
  • PR positive reduction
  • GR general reduction
  • AC Antidepressant as cause
  • the ODQ as referred to herein comprises 3 sections.
  • Section 1 evaluates the experience of emotional blunting during the past week: 12 items, three items from each of the 4 dimensions (NC, ED, PR and GR). Recall period is the last week.
  • Section 2 compares the experience of emotional blunting during the past week to the experience of emotional blunting before their depression: 8 items, 2 from each of the four dimensions, comparing respondents' experiences during the previous week in comparison to their experiences before they developed their illness/problem.
  • Section 3 (6 items) assesses the patient's perception of a relationship between the current antidepressant medication and emotional blunting, as well as whether this effect had affected adherence to treatment. Section 3 describes the dimension AC. Section 3 is only for completion by those respondents currently prescribed antidepressants.
  • ODQ Oxford Depression Questionnaire
  • the ODQ comprises the following questions.
  • Section 1 All my emotions, both 'pleasant' and 'unpleasant', are 'toned down'; I don't fully enjoy things that should give me pleasure, such as beautiful places or things or music; I care less about other people's feelings than I think I should; Because I don't care so much about things, I'm having problems at home; Unpleasant emotions, such as sadness, disappointment, and upset, feel toned down or different in some way; I don't look forward to things with eager anticipation; I don't have much sympathy for people; I feel 'spaced out' and distant from the world around me; My emotions lack intensity; I don't have the passion and enthusiasm for life that I should; Other people being upset doesn't affect me; Because I don't care so much about things, I'm having problems at work or college.
  • Section 2 Day to day life just doesn't have the same emotional impact on me that it did before my illness/problem; I don't experience pleasant emotions as much as I did before I developed my illness/problem; I don't react to other people's emotions (such as their sadness, anger or upset) as much as I did before my illness/problem; I don't care as much about my day to day responsibilities as I did before I developed my illness/problem; My emotions are numbed/dulled/flattened compared to before I developed my illness/problem;
  • the antidepressant is preventing me from feeling my emotions in some way; The antidepressant seems to make me just not care about things that should matter to me; The antidepressant seems to make me feel emotionally disconnected from people around me; The antidepressant is preventing me from feeling pleasant emotions; The antidepressant changes the way that I experience my emotions in a way that is unhelpful/not helpful to me at the moment; I have considered stopping (or have already stopped) my antidepressant because of its emotional side-effects.
  • the term "or equivalent" as used herein in connection with the ODQ scale means that the ODQ may be replaced by a later version of the questionnaire.
  • the scale and score system should thus be adapted to the updated scale, and the guidelines of the ODQ scale as provided with the new version.
  • ODQ guideline or similar phrases as used herein means the guidance provided with the licence for the ODQ, which guide the user of the ODQ regarding which questions to ask and how to score them, including the cut off values for when emotional blunting is present and when not.
  • patient-reported signs and/or symptoms of emotional blunting may be collected by the one or more of the following standardized questionnaires ODQ, MEI, or SDS.
  • patient-reported signs and/or symptoms of emotional blunting may be collected by at least the ODQ.
  • emotional blunting is evaluated by using the guidelines as set forth in The American Psychiatric Association's Diagnostic Statistical Manual's definition of numbing and avoidance.
  • patient-reported signs and/or symptoms of emotional blunting may be collected by the one or more of the following standardized questionnaires: ODQ, 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.
  • PANSS Positive and Negative Schizophrenia Symptoms Scale
  • the presence of emotional blunting can be evaluated clinically with, e.g., tests and assessment methods described herein.
  • patient-reported signs, symptoms, and/or functional consequences of emotional blunting may be collected by one or more of the following standardized questionnaires: ODQ, MEI, and SDS.
  • patient-reported signs and/or symptoms of emotional blunting may be collected by the ODQ.
  • patient-reported signs, symptoms and/or functional consequences of emotional blunting may include collection of information by the one or more of the following standardized questionnaires: ODQ, MEI, and SDS.
  • patient-reported signs and/or symptoms of emotional blunting may be collected by the ODQ.
  • patient-reported signs, and/or symptoms of emotional blunting may include collection of information by the one or more of the following standardized questionnaires: ODQ or MEI.
  • patient- reported signs and/or symptoms of emotional blunting may be collected by the ODQ.
  • the clinician-rated assessment of signs and symptoms of emotional blunting may include collection of information by one or more of the following standardized methods: Montgomery and Asberg Depression Rating Scale ("MADRS”), Clinical Global Impression-Severity of Illness (“CGI-S”), and Clinical Global Impression-Global Improvement (“CGI-I”).
  • MADRS Montgomery and Asberg Depression Rating Scale
  • CGI-S Clinical Global Impression-Severity of Illness
  • CGI-I Clinical Global Impression-Global Improvement
  • the clinician-rated assessment of signs and symptoms of emotional blunting may include collection of information by one or more of the following standardized methods: CGI-S and CGI-I.
  • the presence of emotional blunting can be evaluated clinically with, e.g., tests and assessment methods described herein.
  • patient-reported signs, and/or symptoms of emotional blunting may be collected by the one or more of the following standardized questionnaires: ODQ and MEI.
  • patient-reported signs and/or symptoms of emotional blunting may be collected by the ODQ.
  • the clinician-rated assessment of signs and symptoms of emotional blunting may be collected by one or more of the following standardized methods: MADRS, CGI-S, and CGI-I.
  • Numbing is one of four categories of psychiatric disturbance that must be fulfilled for an individual to receive the diagnosis of PTSD.
  • the American Psychiatric Association's Diagnostic Statistical Manual's definition of numbing (and avoidance) includes seven items, any three of which must be present for that category (numbing and avoidance) to be fulfilled. Emotional numbness is specifically represented by two of seven items. One item describes the presence of a restricted range of affect, e.g., the inability to have loving feelings. A second item describes a markedly diminished interest in significant activities.
  • Numbing is defined by this Manual as "persistent avoidance of stimuli associated with the trauma or numbing of general responsiveness (not present before the trauma), as indicated by at least three of the following: (1) efforts to avoid thoughts or feeling associated with the trauma, (2) efforts to avoid activities or situations that arouse recollections of the trauma, (3) inability to recall an important aspect 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) feeling of detachment or estrangement from others, (6) restricted range of affect, e.g., unable to have loving feelings, and (7) sense of foreshortened future, e.g., does not expect to have a career, marriage, children, or a long life.
  • adverse events including signs and symptoms of emotional blunting may recorded or reported using safety assessments, such as generally used for recording of a reporting or diagnosis of adverse events ("AEs").
  • AEs adverse events
  • discontinuation of patients from a treatment due to adverse events associated with emotional blunting may be recorded or reported according to the general methods of the Discontinuation-Emergent Signs and Symptoms Scale ("DESS").
  • symptoms and signs of emotional blunting may be recorded by voice recording and passively collected data from the patient obtained with a cell phone application, such as, e.g., Discovery by Mindstrong.
  • treatment means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder.
  • the term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications.
  • “treating” or “treatment” may lead to, but does not require, complete alleviation of signs and/or symptoms, does not require a cure, and include protocols that may only have a marginal effect on the patient.
  • reduction or “reducing” as used herein includes a decrease, alleviation, or relief in or of symptoms or signs of, e.g., emotional blunting and does not require complete removal of emotional blunting signs and/or symptoms and does not require a cure.
  • prevents or “preventing” as used herein may be interchangeably be used with the term “prophylactic” and means that signs and/or symptoms of a disease or condition can be partly or completely avoided, following specific instructions, treatment regimen or administration of a medicament.
  • a method as described in the aspects and embodiments of this invention may prevent development of signs and symptoms of emotional blunting as a result of treatment of a patient with an antidepressant or may prevent development of signs and symptoms of emotional blunting as a result of the underlying CNS disease or disorder as such, e.g., depression or PTSD. Nonetheless, in some embodiments prophylactic (preventive) and therapeutic (curative) treatment are two separate aspects of the invention.
  • the patient to be treated is preferably a mammal, in particular a human.
  • the Digit Symbol Substitution Test (“DSST”) was initiated over a century ago as an experimental tool to understand human associative learning. Its clinical utility, owing to its brevity and high discriminant validity, was first recognized in the 1940s, and now the DSST is among the most commonly used tests in clinical neuropsychology.
  • the DSST is a paper-and-pencil cognitive test presented on a single sheet of paper that requires a subject to match symbols to numbers according to a key located on the top of the page. The subject copies the symbol into spaces below a row of numbers.
  • the DSST is perhaps the most commonly used test in all of neuropsychology, owing to several inherent properties: brevity, reliability, and the minimal impact of language, culture, and education on test performance.
  • the MEI is a 27-item scale created to assess fatigue and lassitude.
  • the scale was initially developed for the purpose of evaluating interventions to improve motivation and energy in patients with depression, though with further evaluation, its clinical applications could be extended to other patient groups (Fehnel, S. E., Bann, C. M., Hogue, S. L, Kwong, W. J., Mahajan, S. S. (2004) The development and psychometric evaluation of the motivation and energy inventory. Qual. Life. Res. 13, 1321-1336 (incorporated herein by reference in its entirety)).
  • the MEI assesses three factors: mental or cognitive energy, social motivation, and physical energy.
  • the SDS was developed to assess functional impairment in three inter-related domains: work/school, social life, and family life. It is well known and used by researchers and practicing clinicians.
  • the SDS is a patent self-report tool, in which the patient rates the extent to which said domain-responsibilities are impaired by his or her symptoms on a 10 point visual analogue scale, which uses spatio-visual, numeric, and verbal descriptive anchors simultaneously to assess the level of disability.
  • equate dose means that a dose has been reached from which treatment efficacy can be expected and the attempted treatment can be discontinued and/or replaced with another medicament, due to non-response, partial response or inadequate response.
  • An "adequate dose" for a medicament for treating one or more CNS disease or disorder is selected based on an evidence-based doses disclosed in said medicament's label.
  • inadequate response means no response to a treatment with a medicament, partial response to a treatment with a medicament or a response to a medicament revealing signs and symptoms of emotional blunting.
  • developer as used herein and referring to signs and/or symptoms of emotional blunting is meant to describe a change from no 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 of may be evaluated as described herein.
  • Non-limiting examples of one or more signs and/or symptoms of emotional blunting may be an answer "yes" to screening question b) as described herein in the context of an evaluation performed by a practicing clinician or physician evaluation or a rating score equivalent to an ODQ total score of above 30 or more. Such no signs and/or symptoms of may be evaluated as described herein.
  • Non-limiting examples of no signs and/or symptoms of emotional blunting may be an answer "no" to screening question b) as described herein in the context of an evaluation performed by a practicing clinician or physician evaluation or a rating score equivalent to an ODQ total score of 26 or less.
  • worsening of as used herein and referring to signs and/or symptoms of emotional blunting is meant to describe a change from one or more signs and/or symptoms of emotional blunting to a more sever stage of signs and/or symptoms of emotional blunting, such as ratings in the ODQ total score of above about 30 to about 60, about 40 to about 55, or about 50.
  • medicaments such as antidepressants.
  • Such medicaments can affect the serotonin transmission by, e.g., increasing the level of serotonin on several levels. That is, some will affect the reuptake of serotonin, whereas others may inhibit release of serotonin.
  • fast onset when referring to the treatment described herein includes a reduction of signs and symptoms, such as ODQ or MEI score, or an answer "yes” is switched to "no” to screening question b) as described herein in the context of an evaluation performed, within the first 4 weeks of treatment, preferably within 2 or 1 week of treatment.
  • About 50% of patients may experience an effect of the treatment described herein within 1 week of receiving l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof in a dose of about 5 mg per day, about 10 mg per day, or about 20 mg per day, preferably about 10 mg per day or 20 mg per day.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or a pharmaceutically acceptable salts thereof for use in prevention or treatment of emotional blunting in a patient, such as a patient suffering from a CNS disease or disorder.
  • said CNS disease or disorder is selected from the group of psychotic disorders, such as, psychosis, schizophrenia, schizoaffective disorder, schizophreniform disorder, catatonia, delusional disorder; mood disorders, such as bipolar disorder, cyclothymic disorder, major depression, dysthymia, premenstrual dysphoric disorder; and substance use disorders
  • the invention relates to a method of preventing or treating emotional blunting or signs and symptoms thereof in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof, preferably the administration of vortioxetine.
  • the invention relates to a method of preventing or treating emotional blunting or signs and symptoms thereof in a patient, wherein said patient experiences signs and symptoms of emotional blunting, the method comprising administering to a patient in need thereof a therapeutically effective amount of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the invention relates to a method of preventing or treating emotional blunting or signs and symptoms thereof in a patient, wherein said patient experiences signs and symptoms of emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting resulting from an administration of a medicament, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof, the method comprising administering to a patient in need thereof a therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or a pharmaceutically acceptable salts thereof for use in prevention or treatment of emotional blunting in a patient, wherein said patient experiences emotional blunting as part of a CNS disease or disorder or wherein said patient has a history of signs and symptoms of emotional blunting resulting from an administration of a medicament, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salts thereof.
  • the invention relates to a method of preventing or treating emotional blunting or signs and symptoms thereof in a patient who experiences emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting in connection with the administration of a medicament, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof, the method comprising administering to a patient in need thereof a therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the invention relates to a method of preventing or treating emotional blunting in a patient wherein said patient experiences emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting resulting from an administration of a medicament, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof, the method comprising administering to a patient in need thereof a therapeutically effective amount of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the invention relates to a method of preventing or treating emotional blunting in a patient wherein said patient has experienced emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting resulting from an administration of a medicament at an adequate dose, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof, the method comprising administering to a patient in need thereof a therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the invention relates to a method of preventing or treating emotional blunting in a patient wherein said patient experiences emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting resulting from an inadequate response to a medical treatment, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof, the method comprising administering to a patient in need thereof a therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the invention relates to a method of preventing or treating emotional blunting in a patient wherein said patient experiences emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting resulting from an inadequate response to a medical treatment of a CNS disease or disorder, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof, the method comprising administering to a patient in need thereof a therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or a pharmaceutically acceptable salts thereof for use in prevention or treatment of emotional blunting according to any one of the preceding embodiments wherein said emotional blunting is seen in connection with administration of an adequate dose of a medicament for the treatment of one or more CNS diseases or disorders, wherein said one or more CNS diseases or disorders optionally selected from the group of psychotic disorders, such as schizophrenia, schizoaffective disorder, schizophreniform disorder, catatonia, delusional disorder; mood disorders, such as bipolar disorder, cyclothymic disorder, major depression, dysthymia, premenstrual dysphoric disorder; and substance use disorders, wherein said medicament is not l-[2-(2,4-dimethylphenylsulfanyl)- phenyljpiperazine or a pharmaceutically acceptable salts thereof and wherein said adequate dose of said medicament is a dose as described
  • said medicament or medical treatment of a CNS disease or disorder which may result in emotional blunting due to an inadequate response to said medicament or medical treatment said medicament or medical treatment has an enhancing effect on serotonergic transmission.
  • said medicament or medical treatment of a CNS disease or disorder which may result in emotional blunting due to an inadequate response to said medicament or medical treatment said medicament or medical treatment has an enhancing effect on serotonergic transmission, without affecting other neurotransmitters.
  • said medicament or medical treatment of a CNS disease or disorder which may result in emotional blunting due to an inadequate response to said medicament or medical treatment
  • said medicament or medical treatment is selected from the classes of SSRIs or SNRIs.
  • said medicament or medical treatment of a CNS disease or disorder which may result in emotional blunting due to an inadequate response to said medicament or medical treatment
  • said medicament or medical treatment is a SSRI.
  • said medicament or medical treatment of a CNS disease or disorder which may result in emotional blunting due to an inadequate response to said medicament or medical treatment
  • said medicament or medical treatment is a SSRI and is selected from the group consisting of Escitalopram, Paroxetine, Sertraline, and Citalopram.
  • said medicament or medical treatment of a CNS disease or disorder, which may result in emotional blunting due to an inadequate response to said medicament or medical treatment said medicament or medical treatment is a SNRI and is selected from the group consisting of Venlafaxine and Duloxetine.
  • said medicament or medical treatment of a CNS disease or disorder which may result in emotional blunting due to an inadequate response to said medicament or medical treatment
  • said medicament or medical treatment is selected from medicaments used in the treatment of schizophrenia.
  • said medicament or medical treatment of a CNS disease or disorder which may result in emotional blunting due to an inadequate response to said medicament or medical treatment
  • said medicament or medical treatment is selected from medicaments used in the treatment of schizophrenia, wherein such medicaments can be selected from the group of psychiatric disorders, such as psychosis, schizophrenia, schizoaffective disorder, schizophreniform disorder, catatonia, delusional disorder; mood disorders, such as bipolar disorder, cyclothymic disorder, major depression, dysthymia, premenstrual dysphoric disorder; and substance use disorders.
  • said medicament or medical treatment of a CNS disease or disorder which may result in emotional blunting due to an inadequate response to said medicament or medical treatment
  • said medicament or medical treatment is selected from the ATC/DDD WHO class N05A.
  • said medicament or medical treatment of a CNS disease or disorder which may result in emotional blunting due to an inadequate response to said medicament or medical treatment
  • said medicament or medical treatment is selected from the classes of typical or atypical antipsychotic.
  • a patient is treated, including preventive treatment, according to the present invention, by administration of l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof if said patient experiences signs and symptoms of emotional blunting.
  • the below table indicates patient type in the middle column, which may experience emotional blunting and for which a treatment according to this invention may be beneficial.
  • the right column indicates a recommended treatment scheme:
  • a patient is treated according to this invention, wherein a patient and treatment is selected according to the Table directly above to any one of the indicated examples A, A1-A4, and B-O. In some aspects the patient is selected and treated according to any one of the criteria of the Table directly above.
  • the patient is selected and treated according to scenario A of the above table. In some aspects, the patient is selected and treated according to scenario A1 of the above table. In some aspects, the patient is selected and treated according to scenario A2 of the above table. In some aspects, the patient is selected and treated according to scenario A3 of the above table. In some aspects, the patient is selected and treated according to scenario A4 of the above table. In some aspects, the patient is selected and treated according to scenario B of the above table. In some aspects, the patient is selected and treated according to scenario C of the above table. In some aspects, the patient is selected and treated according to scenario D of the above table. In some aspects, the patient is selected and treated according to scenario E of the above table.
  • the patient is selected and treated according to scenario F of the above table. In some aspects, the patient is selected and treated according to scenario G of the above table. In some aspects, the patient is selected and treated according to scenario H of the above table. In some aspects, the patient is selected and treated according to scenario I of the above table.
  • the patient is selected and treated according to scenario J of the above table. In some aspects, the patient is selected and treated according to scenario K of the above table. In some aspects, the patient is selected and treated according to scenario L of the above table. In some aspects, the patient is selected and treated according to scenario M of the above table. In some aspects, the patient is selected and treated according to scenario N of the above table. In some aspects, the patient is selected and treated according to scenario O of the above table.
  • a practicing clinician or physician may decide to apply the method or use for treating emotional blunting as described in aspects and embodiments herein, if an evaluation of the patient confirms that signs and symptoms of emotional blunting are present in said patient.
  • a practicing clinician or physician may decide to apply the method or use for treating emotional blunting as described in aspects and embodiments herein, if an evaluation of the patient confirms that said patient experienced emotional blunting.
  • a practicing clinician or physician may decide to apply the method or use for treating emotional blunting as described in aspects and embodiments herein, if an evaluation of the patient confirms that signs and symptoms of emotional blunting are present in said patient as a result of a treatment with a medicament, wherein said medicament is not l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • a practicing clinician or physician may decide to apply the method or use for treating emotional blunting as described in aspects and embodiments herein, if an evaluation of the patient confirms that signs and symptoms of emotional blunting are present in said patient as a result of a treatment with a medicament, wherein said medicament is not l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof, wherein said method or use for treating emotional blunting as described in aspects and embodiments herein, comprise the steps of:
  • the invention relates to a method of preventing or treating emotional blunting in a patient wherein said patient has a history of showing signs and symptoms of emotional blunting in connection with a CNS disease or disorder or a medical treatment of one or more CNS disease or disorder, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof, the method comprising the steps of: i) evaluation of said patient by a practicing clinician or physician, wherein said evaluation includes
  • step 1) evaluates that signs and symptoms of emotional blunting are present or a risk of developing such signs and symptoms of emotional blunting is present, administering to a patient in need thereof a therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof; and iii) depending on the underlying CNS disease, said practicing clinician or physician evaluates if one or more additional medicaments are administered for the treatment of said one or more CNS disease or disorder or if one or more medicament for the treatment of said one or more CNS disease is discontinued and replaced with administration of a therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof in step 2).
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or a pharmaceutically acceptable salts thereof for use in prevention or treatment of emotional blunting according to any one of the embodiments, wherein a practicing clinician or physician decides to apply the use for treating emotional blunting according to said preceding embodiments, if an evaluation of the patient confirms that signs and symptoms of emotional blunting are present in said patient or a risk of emotional blunting is based on the use of medicaments for treating the CNS disease or disorder is established, optionally such treatment comprises the steps of:
  • the first step is continuation of said medicament, wherein said medicament is not l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salts thereof; or
  • the first step is to continuate any antidepressant or mood stabilizer, if such medicaments have been used in the treatment of said CNS disease or disorder or to maintain the administration of medicaments for the treatment of Schizophrenia or psychosis which are not antidepressants or mood stabilizers.
  • the second step is administering to a patient in need thereof a therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or a pharmaceutically acceptable salts thereof for use in prevention or treatment of emotional blunting according to any one of the preceding embodiments, wherein a practicing clinician or physician decides to apply the use for treating emotional blunting according to said preceding embodiments, if an evaluation of the patient confirms that signs and symptoms of emotional blunting are present in said patient, optionally such treatment comprises the steps of: a) discontinuation of said medicament, wherein said medicament is not l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof; and b) administering to a patient in need thereof a therapeutically effective amount of l-[2- (2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or a pharmaceutically acceptable salts thereof for use in prevention or treatment of emotional blunting according to any one of the preceding embodiments, wherein said medicament is administered for the prevention or treatment of one or more CNS diseases or disorder, or signs and symptoms thereof and wherein said medicament is not l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salts thereof, wherein said emotional blunting is (1) a result of said CNS disease or disorder, (2) a result if inadequate response to said medical treatment, or (3) reported as being caused by an inadequate response of a medical treatment of a CNS disease or disorder.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use in preventing or treating emotional blunting or signs and symptoms thereof in a patient.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use in preventing or treating emotional blunting or signs and symptoms thereof in a patient, wherein said patient experiences signs and symptoms of emotional blunting.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use in preventing or treating emotional blunting or signs and symptoms thereof in a patient, wherein said patient experiences signs and symptoms of emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use in preventing or treating emotional blunting or signs and symptoms thereof in a patient, wherein said patient experiences emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting in connection with the administration of a medicament, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2- (2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use in preventing or treating emotional blunting in a patient wherein said patient experiences emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting resulting from an administration of a medicament, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use in preventing or treating emotional blunting in a patient wherein said patient experiences emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting resulting from an administration of a medicament or treating one or more CNS disease or disorder, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use in preventing or treating emotional blunting in a patient wherein said patient has experienced emotional blunting or wherein said patient has a history of signs and symptoms of emotional blunting resulting from an administration of a medicament at an adequate dose, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2- (2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use in preventing or treating emotional blunting in a patient wherein said patient has not received any treatment for CNS diseases or disorders before experiencing signs and/or symptoms of emotional blunting.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use in preventing or treating emotional blunting in a patient, wherein said patient has a history of signs and symptoms of emotional blunting resulting from an administration of a medicament, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use in preventing or treating emotional blunting in a patient wherein said patient has a history of showing signs and symptoms of emotional blunting in connection with a CNS disease or disorder or a medical treatment of one or more CNS disease or disorder, wherein said medicament resulting in signs and symptoms of emotional blunting in said patient is not l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof, the use comprising the steps of: i) evaluation of said patient by a practicing clinician or physician, wherein said evaluation includes:
  • step 1) evaluates that signs and symptoms of emotional blunting are present or a risk of developing such signs and symptoms of emotional blunting is present, administering to a patient in need thereof a therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof; and iii) depending on the underlying CNS disease, said practicing clinician or physician evaluates if one or more additional medicaments are administered for the treatment of said one or more CNS disease or disorder or if one or more medicament for the treatment of said one or more CNS disease is discontinued and replaced with administration of a therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof in step 2).
  • an adequate dose of said medicament is a dose as described in said medicament's label.
  • a method or the use of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof this invention refer to an adequate dose of a medicament, wherein said medicament is not l-[2- (2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof and wherein adequate dose of said medicament is a dose described in said medicament's label and selected from any one of doses described for efficient treatment in the label of said medicament.
  • said emotional blunting comprises the steps of:
  • said emotional blunting comprises the steps of:
  • the invention relates to 1 -[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use in the treatment of a CNS disease or disorder, wherein said medicament is for use in a patient who has previously received another medication for the treatment of said disease or disorder which medication was ceased, reduced or has to be ceased, due to emotional blunting.
  • the invention relates to 1 -[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use according to the embodiment above, wherein said CNS disease or disorder is depression, such as MDD.
  • the method or l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use in prevention or treatment of emotional blunting is for treating emotional blunting in a patient.
  • said emotional blunting is associated with a CNS disease or disorder.
  • said emotional blunting is associated with an underlying CNS disease or disorder.
  • said medicament is for treatment of one or more CNS diseases or disorder or signs and symptoms hereof and is not l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • said emotional blunting is reported by said patient.
  • said emotional blunting is diagnosed by a practicing clinician or physician.
  • said emotional blunting is reported by said patient, as being caused by of an inadequate response of a medical treatment of a CNS disease or disorder.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or a pharmaceutically acceptable salts thereof for use in prevention or treatment of emotional blunting according to any one of the preceding embodiments, wherein said medicament is provided for the treatment of one or more CNS disease or disorder and wherein said CNS disease or disorder is selected from the group consisting of: MDD, MDE, PTSD, schizophrenia, cognitive impairment, Parkinson's disease, autism, vascular dementia, and multiple system atrophy.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or a pharmaceutically acceptable salts thereof for use in prevention or treatment of emotional blunting according to any one of the preceding embodiments, wherein said medicament is has enhancing effects on serotonergic transmission, optionally selected from the classes of SSRIs or SNRIs.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in prevention or treatment of emotional blunting according to any one of the preceding embodiments, wherein said medicament is reducing the dopaminergic transmission, optionally selected from typical or atypical antipsychotics.
  • said emotional blunting is diagnosed by a practicing clinician or physician by evaluating the patient, wherein said evaluation comprises the steps of: a) starting a conversation with said patient; b) asking the question: "Have you experienced such emotional effects during the last 6 weeks?"; and c) evaluating the response to question b) and concluding if symptoms or signs of emotional blunting is present in said patient.
  • said emotional blunting is diagnosed by a practicing clinician or physician by evaluating the patient, wherein said evaluation comprises the steps of: a) starting a conversation with said patient, explaining the general emotional effects of emotional blunting; b) asking the question: "Have you experienced such emotional effects during the last 6 weeks?"; and c) evaluating the response to question b) and concluding if symptoms or signs of emotional blunting is present in said patient.
  • said emotional blunting is diagnosed by a practicing clinician or physician by evaluating the patient, wherein said evaluation comprises the steps of: a) starting a conversation with said patient, explaining the general emotional effects of emotional blunting, wherein said explaining can comprise information to the patient that: Emotional effects vary, but may include, for example, feeling emotionally "numbed” or “blunted” in some way; lacking positive emotions or negative emotions; feeling detached from the world around you; or “just not caring” about things that you used to care about; b) asking the question: "Have you experienced such emotional effects during the last 6 weeks?"; and c) evaluating the response to question b) and concluding if symptoms or signs of emotional blunting is present in said patient.
  • step c) of said practicing clinician or physician's evaluation leads to the conclusion of the presence of emotional blunting, if said patient's answer to the question asked in step b) is "yes.”
  • said emotional blunting is diagnosed by a practicing clinician or physician by evaluating the patient, wherein said evaluation comprises the steps of: a) explaining to said patient that: Emotional effects vary, but may include, for example, feeling emotionally “numbed” or “blunted” in some way; lacking positive emotions or negative emotions; feeling detached from the world around you; or “just not caring” about things that you used to care about; b) asking the question: "Have you experienced such emotional effects during the last 6 weeks?"; and c) evaluating the response to question b), where if question b) was answered with a "yes,” concluding that symptoms or signs of emotional blunting is present in said patient.
  • said steps a)-c) of said practicing clinician or physician's evaluation may be supplemented or replaced by an evaluated according to or equivalent to the ODQ scale and ODQ total score, wherein said ODQ total score is calculated based on the ODQ guidelines.
  • said steps a)-c) of said practicing clinician or physician's evaluation may be supplemented or replaced by an evaluation according to or equivalent to the ODQ scale and wherein the ODQ total score is 30 points or more, wherein said ODQ total score is calculated based on the ODQguidelines.
  • said steps a)-c) of said practicing clinician or physician's evaluation may be supplemented or replaced by an evaluation according to or equivalent to the ODQ scale and wherein the ODQ total score is 40 points or more, wherein said ODQ total score is calculated based on the ODQguidelines.
  • said steps a)-c) of said practicing clinician or physician's evaluation may be supplemented or replaced by an evaluation according to or equivalent to the ODQ scale and wherein the ODQ total score is 50 points or more, wherein said ODQ total score is calculated based on the ODQguidelines.
  • said steps a)-c) of said practicing clinician or physician's evaluation may be supplemented or replaced by an evaluation according to or equivalent to the ODQ scale and wherein the ODQ total score is 70 points or more, wherein said ODQ total score is calculated based on the ODQguidelines.
  • said steps a)-c) of said practicing clinician or physician's evaluation may be supplemented or replaced by an evaluation according to or equivalent to the ODQ scale and wherein the ODQ total score is 90 points or more, wherein said ODQ total score is calculated based on the ODQguidelines.
  • said emotional blunting in seen in combination with a total MEI total score of about 45 or less, wherein said MEI total score is evaluated according to the guideline of said MEI.
  • emotional blunting is seen in combination with a MEI total score of about 40 or less, wherein said MEI total score is calculated according to the guideline of said MEI.
  • said emotional blunting is seen in combination with a MEI total score of about 30 or less, wherein said MEI total score is calculated according to the guideline of said MEI.
  • said emotional blunting is seen in combination with a total SDS total score of about 15 or more, wherein said SDS total score is calculated according to the guideline of said SDS. In some embodiments, said emotional blunting is seen in combination with a total SDS total score of about 20 or more, wherein said SDS total score is calculated according to the guideline of said SDS.
  • said emotional blunting is seen in combination with a total SDS total score of about 25 or more, wherein said SDS total score is calculated according to the guideline of said SDS.
  • said steps a)-c) of said practicing clinician or physician's evaluation may be supplemented or replaced by an evaluated according to or equivalent to the SANS scale and relevant scores are calculated based on the guidelines of said SANS.
  • said steps a)-c) of said practicing clinician or physician's evaluation may be supplemented or replaced by an evaluated according to or equivalent to the CAINS scale and relevant scores are calculated based on the guidelines of said CAINS.
  • said steps a)-c) of said practicing clinician or physician's evaluation may be supplemented or replaced by an evaluated according to or equivalent to the BNSS scale and relevant scores are calculated based on the guidelines of said BNSS.
  • said steps a)-c) of said practicing clinician or physician's evaluation may be supplemented or replaced by an evaluated according to or equivalent to the PANSS scale and relevant scores are calculated based on the guidelines of said PANSS.
  • said steps a)-c) of said practicing clinician or physician's evaluation may be supplemented or replaced by an evaluated according to or equivalent to the RSEB scale and relevant scores are calculated based on the guidelines
  • said steps a)-c) of said practicing clinician or physician's evaluation may be supplemented or replaced by an evaluated according to or equivalent to The American Psychiatric Association's Diagnostic Statistical Manual's definition of numbing and avoidance.
  • said steps a)-c) of said practicing clinician or physician's evaluation may be supplemented or replaced by an evaluated according to or equivalent to The American Psychiatric Association's Diagnostic Statistical Manual's definition of numbing and avoidance comprising the steps of the steps of: i) Providing to said patient a questionnaire regarding the experience of one or more of:
  • said steps a)-c) of said practicing clinician or physician's evaluation may be supplemented or replaced by an evaluated according to or equivalent to The American Psychiatric Association's Diagnostic Statistical Manual's definition of numbing and avoidance comprising the steps of: i) providing to the patient a questionnaire comprising one or more of the questions according to The American Psychiatric Association's Diagnostic Statistical Manual's definition of numbing and avoidance, including one of more of the following items:
  • said method or treatment is a fast-onset method or use for the treatment of emotional blunting.
  • said method or use described herein is a fast-onset method or use for the treatment of emotional blunting, wherein a reduction of signs or symptoms is detectable within one week by either the patient or evaluated by the doctor of, e.g., questionnaires answered by the patient.
  • said method or use described herein is a fast-onset method or use for the treatment of emotional blunting, wherein a reduction of signs or symptoms is detectable within two weeks by either the patient or evaluated by the doctor of, e.g., questionnaires answered by the patient.
  • said ODQ total score is reduced by about 6.5 to about 13 points within about one week of administration of said therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • said ODQ total score is reduced by about 15 to about 25 points within about four weeks of administration of said therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • said ODQ total score is reduced by about 17.6 to about 24.8 points within about four weeks of administration of said therapeutically effective amount of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • said ODQ total score is reduced by about 25 to about 30 points within about eight weeks of administration of said therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof. In some embodiments, wherein said method or use as described herein is applied, said ODQ total score is reduced by about 26 to about 29.8 points within about eight weeks of administration of said therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • said ODQ total score is reduced by about 30 points or more after about eight weeks of administration of said therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • said MEI total score is increased by about 18 to about 30 points within about four weeks of administration of said therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • said MEI total score is increased by about 18.8 to about 28.3 points within about four weeks of administration of said therapeutically effective amount of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • said MEI total score is increased by about 28 to about 40 points within about eight weeks of administration of said therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • said MEI total score is increased by about 28.9 to about 39.7 points within about eight weeks of administration of said therapeutically effective amount of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • said MEI total score is increased by about 40 points or more after about eight weeks of administration of said therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • said SDS total score is reduced by about 5 to about 10 points within about eight weeks of administration of said therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • said SDS total score is reduced by about 5.9 to about 9.5 points within about eight weeks of administration of said therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • said SDS total score is reduced by about 10 points or more after about eight weeks of administration of said therapeutically effective amount of l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof.
  • about 50% of said patients answer "no" to the screening question describes as item b) in aspects and embodiments herein and reads as follows: "Have you experienced such emotional effects during the last 6 weeks?", wherein said answer from said patient is "no" after about 8 weeks or more of administration of a therapeutically effective amount of l-[2- (2,4-dimethylphenylsulfanyl)-phenyl] piperazine or pharmaceutically acceptable salts daily at a dose of at least 10 mg/day.
  • said emotional blunting has been reported or diagnosed at least once before onset of any medical treatment.
  • said emotional blunting has been reported or diagnosed at least once before or after onset of any medical treatment.
  • said emotional blunting has been reported or diagnosed once after onset of any medical treatment.
  • said emotional blunting has been reported or diagnosed at least once before onset of any medicament.
  • said emotional blunting has been reported or diagnosed once after onset of any medicament.
  • said method or use or method as described herein said CNS disease or disorder is selected from the group consisting of MDD, MDE, PTSD, schizophrenia, cognitive impairment, Parkinson's disease, autism, vascular dementia, and multiple system atrophy.
  • said CNS disease or disorder is MDD. In some embodiments, said CNS disease or disorder is MDE. In some embodiments, said CNS disease or disorder is PTSD. In some embodiments, said CNS disease or disorder is schizophrenia. In some embodiments, said CNS disease or disorder is Parkinson's disease. In some embodiments, CNS disease or disorder is autism. In some embodiments, said CNS disease or disorder is vascular autism. In some embodiments, said CNS disease or disorder is vascular dementia. In some embodiments, said CNS disease or disorder is Multiple System Atrophy ("MSA"). In some embodiments, said CNS disease or disorder is cognitive impairment. In some embodiments, said cognitive impairment, is associated with Alzheimer's disease or schizophrenia.
  • MSA Multiple System Atrophy
  • said cognitive impairment is diagnosed by a physician, therapist, or physiatrist by the use of a scale similar to DSST. In some embodiments, said Cognitive impairment is reported by a patient.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or a pharmaceutically acceptable salts thereof according to any one of the preceding embodiments, for use in prevention or treatment of emotional blunting or a use according to any one of the preceding embodiments, wherein said patient has not received any treatment for CNS diseases or disorders before experiencing signs and/or symptoms of emotional blunting.
  • said l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof as administered in any of the uses or methods disclosed herein, is a crystalline salt.
  • said l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof as administered in any of the uses or methods disclosed herein is a crystalline salt, wherein said crystalline salt is selected from the group consisting of the hydrobromide (a), hydrobromide (b), and hydrobromide (y).
  • said l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof as administered in any of the uses or methods disclosed herein is a crystalline salt, wherein said crystalline salt is selected from the group consisting of the DL, D- and L-lactic acid addition salt.
  • said l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof as administered in any of the uses or methods disclosed herein is a crystalline salt, wherein said crystalline salt is selected from the group consisting of the DL, D- and L-pyropyroglutamate.
  • said l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof as administered in any of the uses or methods disclosed herein is a crystalline salt, wherein said crystalline salt is selected from the group consisting of the hydrobromide (a), having major XRPD peaks at 5.85 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q), 9.30 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q), 17.49 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q), and 18.58 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q); hydrobromide (b), having major XRPD peaks at 6.89 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q), 9.73 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q), 13.78 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q), and 14.62 ⁇ 0.2, optionally ⁇
  • said l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof as administered in any of the uses or methods disclosed herein is a crystalline salt, wherein said crystalline salt is hydrobromide (b), having major XRPD peaks at 6.89 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q), 9.73 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q), 13.78 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q), and 14.62 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q).
  • said l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof as administered in any of the uses or methods disclosed herein is a crystalline salt, wherein said crystalline salt is selected from the group consisting of the DL-lactic acid addition salt, having major XRPD peaks at 6.01 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q), 10.10 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q), 10.32 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q), 12.06 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q), 12.84 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q), 13.08 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q), and 13.58 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q); L-lactic acid addition salt having major XRPD peaks at 5.33 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2
  • said l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof as administered in any of the uses or methods disclosed herein is a crystalline salt, wherein said crystalline salt is selected from the group consisting of the L-pyroglutamate, having major XRPD peaks at 10.72 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q), 12.14 ( * 2Q) ⁇ 0.2, optionally ⁇ 0.1, 16.22 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q), and 18.59 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q); D-pyroglutamate, having major XRPD peaks at 10.72 ⁇ 0.2, optionally ⁇ 0.1 ( * 2Q), 12.14 ( * 2Q), 16.22 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q), and 18.59 ⁇ 0.2, optionally ⁇ 0.1 ( ° 2Q); and DL
  • said l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof as administered in any of the uses or methods disclosed herein is administered to said patient in a dose between about 1 mg to about 50 mg, preferably about 5 mg, about 10 mg, or about 20 mg per day.
  • said l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof as administered in any of the uses or methods disclosed herein, is administered to said patient in a dose of about 10 mg or about 20 mg per day.
  • said l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof as administered in any of the uses or methods disclosed herein is administered to said patient in a dose of about 10 mg per day in the first week, i.e., day 1 to about day 6 or about day 7, and about 10 mg or about 20mg per day after the first week, i.e., about day 7 or about day 8 for as long as a treatment for which said administration of said l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof is needed by said patient.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or a pharmaceutically acceptable salts thereof according to any one of the preceding embodiments, for use in prevention or treatment of emotional blunting, wherein said l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salts thereof is a crystalline salt, wherein said crystalline salt is selected from the group consisting of the hydrobromide (a), hydrobromide (b), and hydrobromide (y), DL-, D- or L- lactic acid addition salt, or DL-, D-, or L-pyroglutamate salt in a daily dose of about 10 mg or about 20 mg, wherein said patient is administered about 1 Omg per day for about 1 week and either remains on the dose of about 10 mg per day after the first week or increases the dose in agreement with their practicing clinician or physician.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or a pharmaceutically acceptable salts thereof according to any one of the preceding embodiments for use in prevention or treatment of emotional blunting wherein said l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salts thereof is vortioxetine in a daily dose of about 10 mg or about 20 mg, wherein said patient is administered about 10 mg per day for about 1 week and either remains on the dose of about 10 mg per day after the first week or increases the dose, preferably to about 20 mg per day, in agreement with their practicing clinician or physician.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use in prevention, reduction, or treatment of emotional blunting in a patient.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use according to the embodiment above, wherein said patient is suffering from a CNS disease or disorder.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use according to anyone of the embodiments above, wherein said patient experiences emotional blunting as part of a CNS disease or disorder.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use according to any one of the embodiments above, wherein said patient has previously received, or is still receiving, medication for the treatment of said CNS disease.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use according to any one of the embodiments above, said medication resulting in symptom and signs of emotional blunting, wherein said medication was ceased, or has to be ceased, due to emotional blunting.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use according to any one of the embodiments above, wherein said CNS disease or disorder is selected from psychiatric disorders, such as, psychosis, schizophrenia, schizoaffective disorder, schizophreniform disorder, catatonia, delusional disorder; mood disorders, such as bipolar disorder, cyclothymic disorder, major depression, dysthymia, premenstrual dysphoric disorder; and substance use disorders.
  • psychiatric disorders such as, psychosis, schizophrenia, schizoaffective disorder, schizophreniform disorder, catatonia, delusional disorder
  • mood disorders such as bipolar disorder, cyclothymic disorder, major depression, dysthymia, premenstrual dysphoric disorder
  • substance use disorders such as, depression, dysthymia, premenstrual dysphoric disorder.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyljpiperazine or pharmaceutically acceptable salts thereof for use according to any one of the embodiments above wherein said CNS disease or disorder is selected from PTSD, depression including MDD and MDE, cognitive impairment, schizophrenia, psychosis, Parkinson's disease, autism, vascular dementia, and multiple system atrophy.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyljpiperazine or pharmaceutically acceptable salts thereof for use according to any one of the embodiments above, wherein said CNS disease or disorder is selected from MDD and schizophrenia.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyljpiperazine or pharmaceutically acceptable salts thereof for use according to any one of the embodiments above, wherein said medication is a SSRI or a SNRI.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyljpiperazine or pharmaceutically acceptable salts thereof for use according to any one of the embodiments above, wherein said CNS disease or disorder is selected from MDD and schizophrenia, and wherein said medication is a SSRI or a SNRI.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyljpiperazine or pharmaceutically acceptable salts thereof for use according to any one of the embodiments above, wherein said medication is selected from Escitalopram, Fluoxetine, Paroxetine, Sertraline, Venlafaxine, Desvenlafaxine, and Duloxetine.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use according to any one of the embodiments above, wherein said patient has a total score of above BO, such as above 40, such as above 50 in an ODQ.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use according to according to any one of the embodiments above, wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide salt, lactic acid salt, and pyroglutamate salt.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use according to embodiments, wherein said pharmaceutically acceptable salt is selected from the hydrobromide (a) salt, hydrobromide (b) salt, and hydrobromide (y) salt.
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use according to any one of the preceding embodiments, wherein l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof is administered in a unit dose of about 5 mg, about 10 mg, or about 20 mg of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine (calculated as free base).
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use according to any one of the embodiments above, wherein l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof is administered in a dose of about 5 mg/day, about 10 mg/day, or about 20 mg/day of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine (calculated as free base).
  • the invention relates to l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or pharmaceutically acceptable salts thereof for use according to any one of the embodiments above, wherein l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof is administered as oral tablets or oral drops.
  • l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salts thereof is administered as oral tablets or oral drops.
  • WO 0S/0292S2 disclose the compound l-[2- (2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine and pharmaceutically acceptable salts thereof, and methods of making them.
  • ASSAYS describe, in general terms, the study conducted for evaluating the effectiveness of 10 or 20 mg vortioxetine treatment on emotional functioning, i.e., the effect of vortioxetine on emotional blunting.
  • One aspect of the study concerned evaluating the effectiveness of 10 or 20 mg vortioxetine treatment on emotional functioning with MDD with inadequate response to SSRI or SNRI treatment, which are known to induce some degree of emotional numbness or blunting in about 50% of patients.
  • Some aspects of this objective were to evaluate the effectiveness of 10-20 mg flexible-dose vortioxetine after 8 weeks of treatment on motivation and energy, family, social, and work functioning, cognitive functioning, and depressive symptoms, and to evaluate safety of said vortioxetine doses and assess potential discontinuation symptoms following abrupt discontinuation of the previous treatment with SSRI or SNRI and initiation of treatment with vortioxetine.
  • An additional objective was to explore association between digital biomarkers or digital phenotypes and clinical features, which included disease symptoms, functioning, and cognitive performance, however this objective was not explored due to time constraints.
  • the study with the above objective was designed as an interventional, multi-national, multi-site and open label, and flexible dose study.
  • the study comprised an 8-week treatment period with vortioxetine and was followed by a follow up period of 4 weeks for safety assessments. Effectiveness and safety assessments were done at weeks 0, 1, 4, and 8, and unscheduled visits for dose adjustments are allowed any time during the treatment period. An overview of the study design is shown in Figure 1.
  • the patient was treated with SSRI/SNRI monotherapy (citalopram, escitalopram, paroxetine, duloxetine, or venlafaxine) for at least 6 weeks at an adequate dose for the current MDE and with an inadequate response and is a candidate for a switch in the investigator's opinion. Furthermore, the patient had a desire to switch treatment due to this inadequate response and complain about emotional blunting as assessed by the screening question on emotional effects (inclusion criterion 8) and a total score on the ODQ >50.
  • the severity of depressive symptoms as assessed by MADRS total score must have been of >22 and ⁇ 28, corresponding to moderate to severe level of depression.
  • Vortioxetine (Lu AA21004) - 10 or 20 mg/day are oral tablets.
  • the starting dose was 10 mg/day vortioxetine during the first week.
  • the dose may have been increased to 20 mg/day at Visit 2 (Week 1) or remain at 10 mg/day.
  • the dose may have been adjusted (10 or 20 mg/day) at scheduled and unscheduled visits according to the patient's response and the investigator's judgement.
  • Table 1 indicated how many patients increased the dose after week 1 and/or reduced or increased the dose at some point after week 2, e.g., at weeks 2.5, 3, or 4 or any other time before the end of week 8.
  • Table 1 Patients grouped according to the sequence of vortioxetine doses taken during 8 weeks of the study (APTS). About 50% of patients increased the dose to 20 mg/day, about 4 % discontinued the treatment, and about 46% stayed on 10 mg/day of vortioxetine.
  • Patient-reported signs and/or symptoms of emotional blunting were collected by one or more of the following standardized questionnaires: ODQ, MEI, or SDS.
  • Neuropsychological test for evaluating signs and symptoms of emotional blunting were, e.g., DSST.
  • Adverse events including signs and symptoms of emotional blunting may recorded or reported using safety assessments, such as generally used for recording of a reporting or diagnosis of adverse events.
  • Discontinuation of patients from a treatment due to adverse events associated with emotional blunting may be recorded or reported according to the general methods of the Discontinuation-Emergent Signs and Symptoms Scale ("DESS").
  • DESS Discontinuation-Emergent Signs and Symptoms Scale
  • vortioxetine The safety of vortioxetine has been investigated in an extensive clinical trial program, including approximately 12,500 patients (including healthy volunteers) exposed to vortioxetine treatment. Based upon adverse events reporting or diagnosis, evaluation of laboratory safety test values, ECG parameters (including QTc), vital signs, and weight over time relative to placebo, vortioxetine was found to be safe and well-tolerated. The safety profile of vortioxetine in adults and the elderly was found to be similar. Experience from post-marketing use, including an exposure of approximately 2.7 million patient years, confirm the safety profile as found in the clinical trials.
  • Aspect symptoms and signs of emotional blunting may be recorded by voice recording and passively collected data from the patient obtained with a cell phone application, such as, e.g., Discovery by Mindstrong Version 2.2.
  • One endpoint of particular interest of this study was basement of emotional blunting relative to baseline, using the QDQ, a 26-item rating scale assessing four dimensions of emotional blunting, as well as possible attribution to antidepressant treatment.
  • MMRM mixed model for repeated measurements
  • All-patients-enrolled set (“APES”) - all enrolled patients.
  • All-patients-treated set (“APTS”) - all patients in the APES wherein said patient took at least one dose of vortioxetine.
  • the change from baseline in ODQ total score were analyzed using a MMRM approach.
  • the model includes site and week as fixed effects, the baseline score as a continuous covariate and the baseline score-by-week interaction.
  • the analysis was based on all available observations.
  • the adjusted means of the model will be presented with two-sided 95% confidence intervals ("Cls").
  • Descriptive statistics will be presented for the DESS total score at Baseline and Week 1 with frequency tables for discontinuation emergent symptoms per DESS item.
  • the following examples show the results of the clinical trial methods described above.
  • Example 1 Evaluation on emotional blunting by ODQ Total Score in patients with MDD wherein said patient experienced an inadequate response to SSRI or SNRI treatment and wherein said patient was switched to a treatment with 10-20 mg vortioxetine.
  • the ODQ total score starting at about 90 was reduced by about 30 points at week 8, thus a relative reduction of the ODQ Score by a third.
  • Patients switched from SSRI or SNRI to vortioxetine felt relief of the emotional blunting within the first week of switching to vortioxetine 10 mg treatment.
  • Example 2 Evaluation of ODQ domain score domains in patients with MDD wherein said patient experienced an inadequate response to SSRI or SNRI treatment and wherein said patient was switched to a treatment with 10-20 mg vortioxetine.
  • Table 8 Change from Baseline in ODQ total score without AC (FAS, MMRM). The ODQ Section 1+2 score starting at about 74 was reduced by about 25 points at week 8.
  • Example 3 Evaluation of Screening Question on emotional effects in patients with MDD wherein said patient experienced an inadequate response to SSRI or SNRI treatment and wherein said patient was switched to a treatment with 10-20 mg vortioxetine.
  • Example 4 Evaluation of MADRS in patients with MDD wherein said patient experienced an inadequate response to SSRI or SNRI treatment and wherein said patient was switched to a treatment with 10-20 mg vortioxetine.
  • the total MADRS Score baseline (FAS, MMRM) from about 25 was reduced by about 14 points over the course of 8 weeks after switching the patients to vortioxetine treatment.
  • Response defined as at least 50% reduction in total MADRS score from baseline (FAS, observed cases (OC)) was registered in about 62% of patients at week 8.
  • Remission defined as a MADRS total score (FAS, OC) of 10 or less at week 8 was registered to about 47%.
  • Example 5 Evaluation of CGI-S of patients with MDD wherein said patient experienced an inadequate response to SSRI or SNRI treatment and wherein said patient was switched to a treatment with 10-20 mg vortioxetine.
  • Example 6 Evaluation of MEI in patients with MDD wherein said patient experienced an inadequate response to SSRI or SNRI treatment and wherein said patient was switched to a treatment with 10-20 mg vortioxetine.
  • the MEI total score starting at about 44 was increased by about 34 points at week 8, thus a relative increase of the MEI Score by more than 85%.
  • Patients switched from SSRI to SNRI to vortioxetine felt an increase in levels of motivation and energy.
  • Tables 11-13 provide insight into the MEI total sub scores; mental and cognitive energy score, Social Motivation score, and physical energy score (FAS, MMRM).
  • Table 11. Change from Baseline in MEI sub score Mental and cognitive energy score (FAS, MMRM). The Mental and cognitive energy score starting at about 21 was increased by about 15 points at week 8.
  • Table 12. Change from Baseline in MEI sub score Social Motivation score (FAS, MMRM). The Social Motivation score starting at about 14 was increased by about 10 points at week 8.
  • Table IB Change from Baseline in MEI sub score physical energy (FAS, MMRM). The physical energy score starting at about 9 was increased by about 10 points at week 8.
  • Example 8 Evaluation of SDS in patients with MDD wherein said patient experienced an inadequate response to SSRI or SNRI treatment and wherein said patient was switched to a treatment with 10-20 mg vortioxetine.
  • Table 14 provides insight into the SDS total Score.
  • Table 14 Change from Baseline in SDS (FAS, MMRM). The SDS total score starting at about 21 was decreased by about 8 points at week 8.
  • the above data supports that the total disability score covering activities at work, at home, and social life is improved after 8 weeks of treatment with vortioxetine.
  • Example 9 Evaluation of SDS sub scores in patients with MDD wherein said patient experienced an inadequate response to SSRI or SNRI treatment and wherein said patient was switched to a treatment with 10-20 mg vortioxetine
  • Example 10 Evaluation of cognition by DSST scores in patients with MDD wherein said patient experienced an inadequate response to SSRI or SNRI treatment and wherein said patient was switched to a treatment with 10-20 mg vortioxetine.
  • Example 11 Evaluation of correlation between MEI total Score and ODQ total score in patients with MDD wherein said patient experienced an inadequate response to SSRI or SNRI treatment and wherein said patient was switched to a treatment with 10-20 mg vortioxetine.
  • Example 13 Summary of clinical assessment of emotional blunting and partial correlation and mediation analyses.
  • Improvements in motivation and energy assessed using the MEI were substantial and significant already from week 4 and across all subdomains; cognitive and mental energy, social motivation, and physical energy (Table 18; Figure 6).
  • Significant improvement in cognitive performance (DSST) was observed already at week 1 (4.3; p ⁇ 0.0001) and increasing to week 8 (7.8; p ⁇ 0.0001) (Table 18).
  • Significant improvements from baseline to week 8 in overall functioning as measured by the SDS were observed for the total score as well as the single items, most pronouncedly in the Work/School domain (Table 19).
  • Overall depressive symptom resolution as measured by the MADRS total score improved significantly from week 1 (-3.3; p ⁇ 0.0001) and continuously increasing to week 8 (13.8; p ⁇ 0.0001).
  • the rates of response and remission at week 8 as measured by the MADRS were 61.8% and 46.6%, respectively.

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Abstract

La présente invention concerne l'utilisation thérapeutique de la 1-[2-(2,4-diméthylphénylsulfanyl]-phényl]piperazine, notamment pour la prévention, la réduction ou le traitement de l'émoussement émotionnel chez des patients.
PCT/IB2021/000207 2020-04-03 2021-04-02 1-[2-(2,4-diméthylphénylsulfanyl)-phényl]pipérazine pour la prévention ou le traitement de l'émoussement émotionnel WO2021198778A1 (fr)

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AU2021246973A AU2021246973A1 (en) 2020-04-03 2021-04-02 1-(2-(2,4-dimethylphenylsulfanyl)-phenyl)piperazine for prevention or treatment of emotional blunting
JP2022559799A JP2023520016A (ja) 2020-04-03 2021-04-02 感情鈍麻の予防又は処置のための１－［２－（２，４－ジメチルフェニルスルファニル）－フェニル］ピペラジン
KR1020227037929A KR20220163997A (ko) 2020-04-03 2021-04-02 정서적 둔마의 예방 또는 치료를 위한 1-[2-(2,4-디메틸페닐설파닐)-페닐]피페라진

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003029232A1 (fr) 2001-10-04 2003-04-10 H. Lundbeck A/S Derives de phenyl-piperazine en tant qu'inhibiteurs du recaptage de la serotonine
WO2007144005A1 (fr) 2006-06-16 2007-12-21 H. Lundbeck A/S 1-[2-(2, 4-diméthylphénylsulfanyl)-phényl]pipérazine comme composé présentant une activité sur la sérotonine, 5-ht3 et 5-ht1a pour le traitement du déficit cognitif
WO2009062517A1 (fr) 2007-11-13 2009-05-22 H. Lundbeck A/S Utilisations thérapeutiques de composés possédant une activité combinée sur sert, 5-ht3 et 5-ht1a
WO2010121621A1 (fr) 2009-04-24 2010-10-28 H. Lundbeck A/S Formulations liquides de sels de 1-[2-(2,4-diméthylphénylsulfanyl)- phényl]pipérazine
WO2016180870A1 (fr) 2015-05-13 2016-11-17 H. Lundbeck A/S Pyroglutamate de vortioxetine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003029232A1 (fr) 2001-10-04 2003-04-10 H. Lundbeck A/S Derives de phenyl-piperazine en tant qu'inhibiteurs du recaptage de la serotonine
WO2007144005A1 (fr) 2006-06-16 2007-12-21 H. Lundbeck A/S 1-[2-(2, 4-diméthylphénylsulfanyl)-phényl]pipérazine comme composé présentant une activité sur la sérotonine, 5-ht3 et 5-ht1a pour le traitement du déficit cognitif
WO2009062517A1 (fr) 2007-11-13 2009-05-22 H. Lundbeck A/S Utilisations thérapeutiques de composés possédant une activité combinée sur sert, 5-ht3 et 5-ht1a
WO2010121621A1 (fr) 2009-04-24 2010-10-28 H. Lundbeck A/S Formulations liquides de sels de 1-[2-(2,4-diméthylphénylsulfanyl)- phényl]pipérazine
WO2016180870A1 (fr) 2015-05-13 2016-11-17 H. Lundbeck A/S Pyroglutamate de vortioxetine

Non-Patent Citations (60)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "Study With Vortioxetine on Emotional Functioning in Patients With Depression - Tabular View - ClinicalTrials.gov", 8 February 2019 (2019-02-08), XP055729266, Retrieved from the Internet <URL:https://clinicaltrials.gov/ct2/show/record/NCT03835715> [retrieved on 20200909] *
BAJOR LATICLEA ANOSSER DN, HARV. REV. PSYCHIATRY, vol. 19, 2011, pages 240 - 258
BANG-ANDERSEN BRUHLAND TJORGENSEN MSMITH GFREDERIKSEN KJENSEN 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., vol. 54, 2011, pages 3206 - 3221, XP055058222, DOI: 10.1021/jm101459g
BING CAO ET AL: "The Efficacy of Vortioxetine on Anhedonia in Patients With Major Depressive Disorder", FRONTIERS IN PSYCHIATRY, vol. 10, 31 January 2019 (2019-01-31), XP055729092, ISSN: 1664-0640, DOI: 10.3389/fpsyt.2019.00017 *
BLANCHARD JJCOHEN AS: "The structure of negative symptoms within schizophrenia: implications for assessment", SCHIZOPHR BULL, vol. 32, 2006, pages 238 - 245
BLIER, INT. J. NEUROPSYCHOPHARMACOL., vol. 17, 2014, pages 997 - 1008
BOBES J. ET AL., J. CLIN. PSYCHIATRY, vol. 71, no. 3, 2010, pages 280 - 286
BUCKNER ET AL., PSYCHIATRY RES., vol. 159, 2008, pages 25 - 30
CAO ET AL., FRONTIERS IN PSYCHIATRY, vol. 10, 2019, pages 17
CAO ET AL., PROG NEUROPSYHOPHARMACOL BIOL. PSYCHIATRY, 2019
CAO ET AL., PROG. NEUROPSYHOPHARMACOL. BIOL. PSYCHIATRY, vol. 92, 2019, pages 109 - 117
CHRISTIAN DE BODINATET, JOURNAL OF NEUROPSYCHOPHARMACOLOGY, vol. 16, no. 10, 2013, pages 2219 - 2234
CONSTANTINO JNGRUBER CPDAVIS SHAYES SPASSANANTE NPRZYBECK T: "The factor structure of autistic traits", J. CHILD PSYCHOL. PSYCHIATRY, vol. 45, 2004, pages 719 - 726
CORRUBLE ET AL., INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, vol. 16, no. 10, 2013, pages 2219 - 2234
D'AGOSTINO AENGLISH CDREY JA: "Vortioxetine (Brintellix): a new serotonergic antidepressant", P T., vol. 40, no. 1, 2015, pages 36 - 40
DALE EBANG-ANDERSEN BSANCHEZ C: "Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs", BIOCHEM PHARMACOL, vol. 95, no. 2, 2015, pages 81 - 97, XP055729104, DOI: 10.1016/j.bcp.2015.03.011
EMMANUELLE CORRUBLE ET AL: "Abstract", INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, vol. 16, no. 10, 1 November 2013 (2013-11-01), Cambridge, pages 2219 - 2234, XP055729756, ISSN: 1461-1457, DOI: 10.1017/S1461145713000679 *
ESPERIDIAO-ANTONIO ET AL., INT REV PSYCHIATRY, vol. 29, 2017, pages 293 - 307
FAGIOLINI ANDREA ET AL: "Effectiveness of Vortioxetine on Emotional Blunting in Patients with Major Depressive Disorder with inadequate response to SSRI/SNRI treatment", JOURNAL OF AFFECTIVE DISORDERS., vol. 283, 1 March 2021 (2021-03-01), NL, pages 472 - 479, XP055822809, ISSN: 0165-0327, DOI: 10.1016/j.jad.2020.11.106 *
FEHNEL, S. E.BANN, C. M.HOGUE, S. L.KWONG, W. J.MAHAJAN, S. S.: "The development and psychometric evaluation of the motivation and energy inventory", QUAL. LIFE. RES., vol. 13, 2004, pages 1321 - 1336
FETONI VSOLIVERI PMONZA DTESTA DGIROTTI F: "Affective symptoms in multiple system atrophy and Parkinson's disease: response to levodopa therapy", J. NEUROL. NEUROSURG. PSYCHIATRY., vol. 66, 1999, pages 541 - 544
FRANKEN ET AL., J. AFFECT. DISORD., vol. 99, 2007, pages 83 - 89
GARDIER AMLEPOUL ETROUVIN JHCHANUT EDESSALLES MCJACQUOT 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., vol. 54, 1994, pages 151 - 156
GOODWIN ET AL., JOURNAL OF AFFECTIVE DISCORDERS, vol. 211, 2017, pages 31 - 35
GOODWIN G M ET AL: "Emotional blunting with antidepressant treatments: A survey among depressed patients", JOURNAL OF AFFECTIVE DISORDERS, ELSEVIER BIOCHEMICAL PRESS, AMSTERDAM, NL, vol. 221, 6 June 2017 (2017-06-06), pages 31 - 35, XP085129248, ISSN: 0165-0327, DOI: 10.1016/J.JAD.2017.05.048 *
GOODWIN GMPRICE JBODINAT CDLAREDO J.: "Emotional blunting with antidepressant treatments: A survey among depressed patients", J AFFECT DISORD, vol. 221, 2017, pages 31 - 35, XP085129248, DOI: 10.1016/j.jad.2017.05.048
GOODWIN GMPRICE JBODINAT CDLAREDO J.: "Emotional blunting with antidepressant treatments: A survey among depressed patients", J. AFFECT. DISORD., vol. 221, 2017, pages 31 - 35, XP085129248, DOI: 10.1016/j.jad.2017.05.048
JONATHAN PRICE ET AL.: "The Oxford Quastionaire on Emotional Side-Effects on Atidepressants (OQuESA): Development, validity, reliability and sensetivity change", JOURNAL OF AFFECTIVE DISCORDERS, vol. 140, 2012, pages 66 - 74
JONATHAN PRICE ET AL: "The Oxford Questionnaire on the Emotional Side-effects of Antidepressants (OQuESA): Development, validity, reliability and sensitivity to change", JOURNAL OF AFFECTIVE DISORDERS, ELSEVIER BIOCHEMICAL PRESS, AMSTERDAM, NL, vol. 140, no. 1, 27 January 2012 (2012-01-27), pages 66 - 74, XP028429843, ISSN: 0165-0327, [retrieved on 20120207], DOI: 10.1016/J.JAD.2012.01.030 *
JONES JDBUTTERFIELD LCSONG W ET AL., J NEUROPSYCHIATRY CLIN. NEUROSCI, vol. 27, no. 3, 2015, pages 213 - 8
JOUVENT RLE HOUEZEC JPAYAN 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, vol. 79, no. 3, 1998, pages 267 - 275
KAWAHARA YKAWAHARA HKANEKO FTANAKA M: "Long-term administration of citalopram reduces basal and stress-induced extracellular noradrenaline levels in rat brain", PSYCHOPHARMACOLOGY (BERL, vol. 194, 2007, pages 73 - 81, XP019537362, DOI: 10.1007/s00213-007-0826-8
KILIAN, S.ASMAL, L.GOOSEN, A.CHILIZA, B.PHAHLADIRA, L.EMSLEY, R.: "Instruments measuring blunted affect in schizophrenia: A systematic review", PLOS ONE, vol. 10, no. 6, 2015
LANCU IPOREH ALEHMAN BSHAMIR EKOTLER M: "The positive and negative symptom questionnaire: a self-report scale in schizophrenia", COMPREHENSIVE PSYCHIATRY, vol. 46, 2005, pages 61 - 66, XP004680096, DOI: 10.1016/j.comppsych.2004.07.014
LANE RM: "Restoration of positive mood states in major depression as a potential drug development target", J. PSYCHOPHARMACOL., vol. 28, no. 6, 2014, pages 527 - 535
LOAS ET AL., COMPR. PSYCHIATRY, vol. 35, 1994, pages 366 - 372
M RK APEHRSON ABRENNUM LTNIELSEN SMZHONG HLASSEN AB ET AL.: "Pharmacological effects of Lu AA21004: a novel multimodal compound for the treatment of Major Depressive Disorder", J PHARMACOL EXP THER, vol. 340, no. 3, 2012, pages 666 - 675, XP055162331, DOI: 10.1124/jpet.111.189068
MUCCI A. ET AL., SCHIZOPHR. RES., vol. 186, 2017, pages 19 - 28
MUCCI A. ET AL., SCHIZOPHRENIA RESEARCH, vol. 186, 2017, pages 19 - 28
PAN ET AL., CURR. PHARM. DES., vol. 23, 2017, pages 2065 - 2072
PATEL KALLEN SHAQUE MNANGELESCU IBAUMEISTER DTRACY DK., THER. ADV. PSYCHOPHARMACOL., vol. 6, no. 2, 2016, pages 99 - 144
PENG LI ET AL., CURRENT TOPICS IN MEDICINAL CHEMISTRY, vol. 16, 2016, pages 3385 - 3403
PERALTA VCUESTA MJ: "Psychometric properties of the positive and negative syndrome scale (PANSS) in schizophrenia", PSYCHIATRY RESEARCH, vol. 53, 1994, pages 31 - 40
PRICE JCOLE VGOODWIN GM., BR. J. PSYCHIATRY, vol. 195, no. 3, 2009, pages 211 - 217
RABINOWITZ J. ET AL., SCHIZOPHR RES., vol. 150, no. 2-3, 2013, pages 339 - 342
RABINOWITZ J. ET AL., SCHIZOPHR. RES., vol. 150, no. 2-3, 2013, pages 339 - 342
RIZVI SJPIZZAGALLI DASPROULE BAKENNEDY SH, NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS, vol. 65, 2016, pages 21 - 35
ROBERTSON JMTANGUAY PEL'ECUYER SSIMS AWALTRIP C: "Domains of social communication handicap in autism spectrum disorder", J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY., vol. 38, 1999, pages 738 - 745, XP085815299, DOI: 10.1097/00004583-199906000-00022
ROSENBLAT ET AL., J AFFECT. DISORD., vol. 243, 2019, pages 116 - 120
RUSH ET AL., AM. J. PSYCHIATRY, vol. 163, 2006, pages 1905 - 1917
SANSONESANSONE, PSYCHIATRY (EDGMONT, vol. 7, 2010, pages 14 - 18
STERNATKATZMAN, NEUROPSYCHIATR. DIS. TREAT., vol. 12, 2016, pages 2149 - 2164
SULTZER DLLEVIN HSMAHLER MEHIGH WMCUMMINGS JL: "A comparison of psychiatric symptoms in vascular dementia and Alzheimer's disease", AM. J. PSYCHIATRY., vol. 150, 1993, pages 1806 - 1812
SZABO STDE MONTIGNY CBLIER P: "Progressive attenuation of the firing activity of locus coeruleus noradrenergic neurons by sustained administration of selective serotonin reuptake inhibitors", INT J NEUROPSYCHOPHARMACOL, vol. 3, no. 1, 2000, pages 1 - 11
T. SUMIYOSHI, AM.J.PSYCH., vol. 158, 2001, pages 1722 - 1725
TOLL WABARBUI C, OMMEREN, JAMA, vol. 310, 2013, pages 477 - 478
TREMEAU FMALASPINA DDUVAL F ET AL.: "Facial expressiveness in patients with schizophrenia compared to depressed patients and nonpatient comparison subjects", AM. J. PSYCHIATRY., vol. 162, 2005, pages 92 - 101
UHER ET AL., PSYCHOL MED, vol. 42, 2012, pages 967 - 980
WALTER A., PHARMACOTHERAPY FOR POST-TRAUMATIC STRESS DISORDER IN COMBAT VETERANS P T., vol. 37, no. 1, 2012, pages 32 - 38
Y. CHUNG, BRAIN RES., vol. 1023, 2004, pages 54 - 63

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