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USOO83 04431B2

(12) United States Patent (10) Patent No.: US 8,304,431 B2 Buntinx (45) Date of Patent: *Nov. 6, 2012

(54) USE OF D4 AND 5-HT2A ANTAGONISTS, 5,955.459 A 9/1999 Bradley et al. NVERSEAGONSTS OR PARTAL 6,150,353 A 11/2000 Broekkamp et al. 6, 191,133 B1 2/2001 Coppen AGONSTS 6,300,354 B1 10/2001 Steiner et al. 6,358,698 B1 3/2002 Weiner et al. (75) Inventor: Erik Buntinx, Alken (BE) 6,486,153 B1 1 1/2002 Pineiro et al. 2002fOO86899 A1* 7/2002 Sanchez et al...... 514,469 2003/0032636 A1 2/2003 Cremers et al. (73) Assignee: PharmaNeuroBoost N.V., Alken (BE) 2004.0002482 A1 1/2004 Dudley et al. 2004/021381.6 A1 10/2004 Weiner et al. (*) Notice: Subject to any disclaimer, the term of this 2004/0266790 A1 12/2004 Bartlet al. patent is extended or adjusted under 35 2005, 0119248 A1 6/2005 Buntinx 2005, 0119249 A1 6/2005 Buntinx U.S.C. 154(b) by 1007 days. 2005/01 19253 A1 6/2005 Buntinx This patent is Subject to a terminal dis 2005, 0148018 A1 7/2005 Weiner et al. 2005/0203130 A1 9, 2005 Buntinx claimer. 2005/0261278 A1 11/2005 Weiner et al. 2005/0261340 A1 11/2005 Weiner et al. (21) Appl. No.: 10/580,962 2005/0288328 A1 12/2005 Weiner et al. 2006, O199842 A1 9, 2006 Weiner et al. 2006/0264465 A1 11/2006 Weiner et al. (22) PCT Filed: Dec. 2, 2004 2006/0264466 A1 11/2006 Weiner et al. (86). PCT No.: PCT/BE2004/OOO172 2011/O136865 A1 6, 2011 Buntinx (Continued) S371 (c)(1), (2), (4) Date: May 31, 2006 FOREIGN PATENT DOCUMENTS CA 246.1248 9, 2009 (87) PCT Pub. No.: WO2005/053796 (Continued) PCT Pub. Date: Jun. 16, 2005 OTHER PUBLICATIONS (65) Prior Publication Data Van Oekelen et. al., Eur, J. Pharm., 2001, Elsevier Science, vol. 425, US 2007/OO78162 A1 Apr. 5, 2007 pp. 21-32.* Meyer, U. A. J. Pharmacokinetics & Biopharmaceutics, 1996, Ple (30) Foreign Application Priority Data num Publishing Corp., vol. 24, pp. 449-459.* Müller T, entitled “Drug treatment of non-motor symptoms in Parkinson's disease.” Expert Opinion on Pharmacotherapy, 2002, Dec. 2, 2003 (CA) ...... 245.1798 vol. 3, No. 4, pp. 381-388. Dec. 2, 2003 (EP). ... O3447279 PERMAX prescription information, Eli Lilly Company, (http:// Jan. 5, 2004 (EP). ... O4447OO1 www.fda.gov/medwatch/safety/2003/permax Plpdf), revised Oct. Mar. 18, 2004 (CA). ... 246.1248 2, 2003, pp. 1-2.

Mar. 18, 2004 (EP). ... O4447O66 Oct. 21, 2004 (EP) ...... O4O25035 (Continued) Nov. 4, 2004 (JP). 2004-34.9085 Primary Examiner — Shengjun Wang Nov. 15, 2004 (CA) ...... 2487529 Assistant Examiner — Sarah Pihonak (51) Int. Cl. (74) Attorney, Agent, or Firm — Amster, Rothstein & AOIN 43/40 (2006.01) Ebenstein LLP AOIN 43/08 (2006.01) A6 IK3I/445 (2006.01) (57) ABSTRACT A6 IK3I/34 (2006.01) The present invention relates to the use of compounds and CO7D 2II/00 (2006.01) compositions of compounds having D4 and 5-HT2A antago C07D 307/00 (2006.01) nistic, partial agonistic or inverse agonistic activity for the (52) U.S. Cl...... 514/316; 514/469: 546/186; 549/469 treatment of the underlying dysregulation of the emotional (58) Field of Classification Search ...... 514/316, functionality of mental disorders (i.e. affect instability-hyper 514/469: 546/186; 549/469 sensitivity-hyperaesthesia-dissociative phenomena-etc). The See application file for complete search history. invention also relates to methods comprising administering to a patient diagnosed as having a neuropsychiatric disorder a (56) References Cited pharmaceutical composition containing (i) compounds hav ing D4 antagonistic, partial agonistic or inverse agonistic U.S. PATENT DOCUMENTS activity and (ii) compounds having 5-HT2A antagonistic, 4,797.419 A 1, 1989 Moos et al. partial agonistic or inverse agonistic, and (iii) any known 5,364,857 A 11/1994 Bode Greuel medicinal compound and compositions of said compounds. 5,446,070 A 8, 1995 Mantelle The combined D4 and 5-HT2A antagonistic, partial agonistic 5,554,383 A 9, 1996 Dodman 5,635,213 A 6/1997 Nystrom et al. or inverseagonistic effects may reside within the same chemi 5,723.467 A 3, 1998 MeSens et al. cal or biological compound or in two different chemical and/ 5,759,837 A 6/1998 Kuhajda et al. or biological compounds. 5,762,960 A 6, 1998 Dodman 5,780.474. A 7/1998 Peglion et al. 33 Claims, 15 Drawing Sheets US 8,304,431 B2 Page 2

U.S. PATENT DOCUMENTS Carlier PR et al., Synthesis of a Potent Wide-Spectrum -, 2011/0172251 A1 7, 2011 Buntinx Norepinephrine-, -reuptake inhibitor (SNDRI) and a spe 2011/02O7776 A1 8, 2011 Buntinx cies-selective dopamine reuptake inhibitor based on the gamma 2012/0010242 A1 1/2012 Buntinx amino functional group, Bioorgan. Medicin. Chem. Let. 8, 1998, 487-492. FOREIGN PATENT DOCUMENTS Fitzgerald K D et al., entitled “ Augmentation of DE 4039631 A1 6, 1992 Serotonin Reuptake InhibitorTreatment of Pediatric Obsessive Com WO WO98, 11897 A 3, 1998 pulsive Disorder.” Journal of Child and Adolescent WO WO 98.43646 A 10, 1998 Psychopharmacology, vol. 9, No. 2, 1999, 115-123. WO WOOO64441 A 11, 2000 McDougle C J et al., entitled "A Double-blind. Placebo-Dontrolled WO WOO 103694 A1 * 1 2001 Study of Risperidone Addition in Serotonin Reuptake Inhibitor-Re WO WOO1? 41701 A2 * 6, 2001 fractory Obsessive-complusive Disorder.” Arch Gen Psychiatry, vol. WO WOO1f98298 A 12/2001 57. Aug. 2000, 794-801. WO WO O2/O51833. A T 2002 Maina G et al., entitled “ agumentation for treatment OTHER PUBLICATIONS resistant obsessive-compulsive disorder: what if antipsychotic is dis continued.” Int. Clin. Psychopharm, 18, 2003, 23-28. SPTO Office Action dated May 3, 2007 in connection with related Hirose Set al., entitled "An Open Pilot Study Combining Risperidone .S. Appl. No. 10/803,793, filed Mar. 18, 2004. and a Selective Serotonin Reuptake Inhibitor as Initial Antidepresant SPTO Office Action dated Aug. 10, 2007 in connection with related Therapy,” J. Clin. Psych. 63, 2002, 733-736. .S. Appl. No. 10/984,683, filed Nov. 9, 2004. Truffinet Petal. Placebo-controlled study of the D475-HT2A antago SPTO Office Action dated Oct. 2, 2007 in connection with related nist in the treatment of . Am J. Psychiatry .S. Appl. No. 10/752,423, filed Jan. 6, 2004. 156: 419-425, 1999. 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US 8,304,431 B2 1. 2 USE OF D4AND 5-HT2A ANTAGONISTS, and Practice, 9, 85-90; Linehan, M. M., 1993, Cognitive INVERSEAGONSTS OR PARTAL behavioral treatment of borderline personality disorder, New AGONSTS York, The Guilford Press; Gratz, K. L., Roemer, L., 2001 & 2004, Multidimensional assessment of emotion regulation CROSS REFERENCE TO RELATED and dysregulation. development, factor structure, and initial APPLICATIONS validation of the Difficulties in Emotion Regulation Scale, Annual meeting of the Association for Advancement of This application is a national stage entry under 35 U.S.C. Behavior Therapy, November 2001 & Journal of Psychopa S371 of PCT International Application No. PCT/BE2004/ thology and Behavioral Assessment, Vol. 26, No. 1, March 000172, filed Dec. 2, 2004, which claims priority of U.S. 10 2004) besides behavioural and cognitive dysfunctions. D4 patent application Ser. No. 10/725,965, filed Dec. 2, 2003, dopamine receptors (D4DR), almost exclusively present in now U.S. Pat. No. 7,884,096, Canadian Patent Application the mesocortical and mesolimbic systems (O'Malley, K. L., No. 2,451,798, filed Dec. 2, 2003, European Patent Applica Harmon, S., Tang, L., Todd, R. D., The rat dopamine D4 tion No. 03447279.5, filed Dec. 2, 2003, European Patent receptor, sequence, gene structure, and demonstration of Application No. 04447001.1, filed Jan. 5, 2004, U.S. patent 15 expression in the cardiovascular system, New Biol., 4, 137 application Ser. No. 10/752,423, filed Jan. 6, 2004, now U.S. 46, 1992), are in the art known as modulators of emotion and Pat. No. 7,855,195, European Patent Application No. cognition. D4DRagonistic activity gives a behavioural sen 04447066.4, filed Mar. 18, 2004, U.S. patent application Ser. sitisation; D4DR antagonistic activity leads to an emotion No. 10/803,793, filed Mar. 18, 2004, Canadian Patent Appli modulation (Svensson, T. H. Mathé, A. A., cation No. 2,461.248, filed Mar. 18, 2004, European Patent Transmitter Systems, Biological Psychiatry (eds. D'Haenen, Application No. 04025035.9, filed Oct. 21, 2004, Japanese H., et al.), 45-66, 2002, John Wiley & Sons, Ltd). Data dem Patent Application No. 2004-34.9085, filed Nov. 4, 2004, U.S. onstrate that agonism of the dopamine D4 receptors play an patent application Ser. No. 10/984,683, filed Nov. 9, 2004, important role in the induction of behavioral sensitization to and Canadian Patent Application No. 2.487,529, filed Nov. and accompanying adaptations in pre- and 15, 2004. 25 postsynaptic neural systems associated with the mesolimb ocortical dopamine projections (D. L. Feldpausch et al.; The FIELD OF THE INVENTION Journal of Pharmacology and Experimental Therapeutics Vol. 286, Issue 1,497-508, July 1998). The invention relates to the field of neuropsychiatry. More Results suggest that the antagonisms of cortical D2 dopam specifically, the invention relates to the use of compounds, 30 ine receptors are a common target of traditional and atypical which have D4 and 5-HT2A antagonist, inverse agonist or antipsychotics for therapeutic action. Higher in vivo binding partial agonist activity, for the preparation of medicaments. to the D2 receptors in the cortex than in the basal ganglia is Suggested as an indicator of favorable profile for a putative BACKGROUND OF THE INVENTION antipsychotic compound (X. Xiberas and J. L. Martinot: The 35 British Journal of Psychiatry (2001) 179: 503-508). Results Conventionally, mental disorders are divided into types show that dopamine D4 receptor antagonism in the brain does based on criteria sets with defining features. DSM-IV (Ameri not result in the same neurochemical consequences (in can Psychiatric Association, (1993-ISBN 0-89042-061-0)) is creased dopamine metabolism or hyperprolactinemia) the in the art well-known golden standard of such a categori observed with typical neuroleptics (Smite Patel at al., The cal classification. In DSM-IV, there is no assumption that 40 Journal of Pharmacology and Experimental Therapeutics each category of mental disorder is a completely discrete Vol. 283, Issue 2,636-647, 1997). The selective D4 dopamine entity with absolute boundaries dividing it from other mental L-745,870 was ineffective as an antipsy disorders or from no mental disorder. There is also no chotic for the treatment of neuroleptic responsive patients assumption that all individuals described as having the same with acute schizophrenia (Kramer, M. S. et al., Arch. Gen. mental disorder are alike in all important ways. Individuals 45 Psychiatry 1997 December; 54(12):1080). sharing a diagnosis are likely to be heterogeneous even in Finally, in the biological system, mental disorders are regard to the defining features of the diagnosis. Thus, the defined on other levels of abstraction than in the categorical categorical defined mental disorders as mood and anxiety and dimensional system. Structural pathology (e.g. amyloid disorders are having an external and even internal variable plaques in Alzheimer Disease), etiology (e.g. HIV Dementia) co-incidence of symptoms concerning e.g. mood, anxiety, 50 and deviance from a physiological norm (e.g. reduced cere perception, feeding, somatic sensations, sexual functions, bral blood flow) are often used as indicative biological mark sleep, cognitive functioning, impulse control, attention, Sub ers for a mental disorder. The underlying dysregulation of stance use, personality, bereavement, identity, phase of life, various neurotransmittor systems (glutaminergic, GABAer abuse or neglect and other aspects of behavior. gic, cholinergic, monoaminergic (nor-adrenergic, dopamin In a dimensional system, clinical presentations are classi 55 ergic, ), etc.) is the in the art used model for the fied based on quantification of attributes i.e. dysfunctions explanation of the biological determinants of the clinical rather than the assignment to categories and works best in presentation of mental disturbances. It is known that the Sero describing phenomena that are distributed continuously and tonin 2A Receptor (5-HT2A receptor)—which is widespread that do not have clear boundaries. in the Central Nervous System (CNS) has a regulating role Emotion dysregulation is known as Such an attribution or 60 on the dysregulation of various neuro-transmitter systems. dysfunction that plays an important role in the development 5-HT2A agonism gives several behavioural disturbances: and course of mental disorders (Gross, J. J. & Munoz. R. F., 5-HT2A antagonism leads to a governance of mood, Social 1995, Emotion regulation and mental health, Clinical Psy behaviour, anxiety, cognitive function, stress, sleep functions, chology. Science and Practice, 2, 151-164: Mennin, D. S., nociception, sexual functions, feeding and other aspects of Heimberg, R. G., Turk, C. L. & Fresco, D.M., 2002, Applying 65 behaviour (J. E. Leysen (2004) 5-HT2 Receptors, Current an emotion regulation framework to integrative approaches Drug Targets—CNS & Neurological Disorders, 2004, 3, to generalized anxiety disorder; Clinical Psychology. Science 11-26). US 8,304,431 B2 3 4 Dysregulation of the HPA axis (hypothalamic-pituitary disease or disorder with an underlying emotion dysregula adrenal axis) has frequently been reported in patients with tion, characterised in that said compound has (i) a selective psychiatric disorders, and is among the most robustly dem affinity for the Dopamine-4 (D4) receptor with a pKi value onstrated neurobiological changes among psychiatric equal to or higher than 8 towards the D4 receptor and less than patients (D. A. Gutman and C. B. Nemeroff, Neuroendocri 8 towards other Dopamine receptors, and (ii) a selective affin nology, Biological Psychiatry (eds. D'Haenen, H., et al), 99, ity for the 5-HT2A receptor with a pKi value equal to or 2002, John Wiley & Sons, Ltd). The resulting elevated plasma higher than 8 towards the 5-HT2A receptor and less than 8 cortisol concentrations leads to an enhanced binding of sero towards other 5-HT receptors and wherein said compound is tonin for the 5-HT2A receptor (E. A. Young, Mineralocorti administered to a patient in a dose ranging between 5 and 15 coid Receptor Function in Major Depression, Arch. Gen. 10 mg of the active ingredient. Preferably, said compound is Psychiatry, January 2003; 60: 24-28) and thus agonism. pipamperon. Additionally 5-HT2A antagonism gives a des-inhibiting of In a preferred embodiment, in a monotherapeutic context, the inhibitory effect of the 5-HT2A receptor on (i) the the invention relates to the use of a compound as defined 5-HT1A receptor stimulation by serotonin (S. M. Stahl, above, preferably pipamperon, for preparing a medicament Newer Antidepressants and Mood Stabilizers, Essential Psy 15 for treating a disease or disorder selected from the group chopharmacology, 265, University Press; 2 edition (Jun. 15, comprising anxiety disorders, eating disorders, premenstrual 2000); ISBN: 0521646154) and on (ii) the dopamine release syndrome, Somatoform disorders, factitious disorders, disso in the mesocortical systems (S. M. Stahl, Classical Antide ciative disorders, sexual and gender identity disorders, sleep pressants, Serotonin Selective and Noradrenargic Reuptake disorders, adjustment disorders, cognitive disorders, impulse Inhibitors, Essential Psychopharmacology, 233, University control disorders, pervasive development, attention-deficit Press; 2 edition (Jun. 15, 2000); ISBN: 0521646154). and disruptive behaviour disorders, substance-related disor Clinical or real effectiveness of psychopharma is very rare ders, personality disorders, psychological factors affecting via common pooping-out; many treatment-refractory medical conditions, malingering, antisocial behaviour, patients and up to half of patients fail to attain remission (S. bereavement, occupational, identity, phase of life, academic M. Stahl, Essential Psychopharmacology, Depression and 25 problem, problems related to abuse or neglect. Bipolar Disorders, 151, University Press; 2 edition (Jun. 15, According to a further embodiment the invention relates to 2000); ISBN: 0521646,154). Implications of not attaining the use of a first compound as defined above for the prepara remission for Mental Disorders are increased relapse rates, tion of a medicament for treating a mental disease or disorder continuing functional impairment and increased Suicide rate with an underlying emotion dysregulation whereby a second (S.M. Stahl, Essential Psychopharmacology, Depression and 30 compound is administered simultaneously with, separate Bipolar Disorders, 152, University Press; 2 edition (Jun. 15, from or sequential to said first compound to augment the 2000): ISBN: 0521646154). Clinical causes of not attaining therapeutic effect of said second compound on said disease, remission by the Current Psychopharmacological Com or to provide a faster onset of the therapeutic effect of said pounds are inadequate early treatment, underlying emotion second compound on said disease. dysregulation (affecting instability-hypersensitivity-hypera 35 The mental diseases or disorders characterized by an esthesia-dissociative phenomena, etc.) and competitive underlying emotion dysregulation can be grouped into Sub antagonism. There is thus a growing need for a more efficient classes as follows: (i) non-cognitive mental disorders com therapy and more efficient, selective and efficacious medica prising mood disorders, anxiety disorders, psychotic disor ments for treating mental disorders. ders, eating disorders, premenstrual syndrome, Somatoform 40 disorders (excluding pain disorders), factitious disorders, dis SUMMARY OF THE INVENTION Sociative disorders, sexual and gender identity disorders, sleep disorders, adjustment disorders, impulse control disor The present invention relates to the use of compounds and ders, pervasive development disorders, attention-deficit dis pharmaceutical compositions having D4 and 5-HT2A orders, disruptive behaviour disorders, substance-related dis antagonistic, partial agonistic or inverse agonistic activity for 45 orders, personality disorders, psychological factors affecting the treatment of the underlying emotion dysregulation of medical conditions, malingering, antisocial behaviour, mental disorders (e.g. affecting instability-hypersensitivity bereavement, occupational problems, identity problem, hyperaesthesia-dissociative phenomena-etc.) and to methods phase of life problem, academic problem and problems entailing administering to a patient diagnosed as having a related to abuse or neglect; (ii) cognitive diseases comprising mental disorder a pharmaceutical composition containing (i) 50 delirium, Alzheimer Disease, Substance-related persisting compounds having specific high selective D4 and 5-HT2A dementia, Vascular dementia, dementia due to HIV disease, antagonistic, partial agonistic or inverse agonistic activity and dementia due to head trauma, dementia due to Parkinson (ii) a known medicinal compound and/or compositions of Disease, dementia due to Huntington Disease, dementia due compounds. The combined D4 and 5-HT2A antagonistic, to Pick Disease, dementia due to Creutzfeldt-Jacob Disease, partial agonistic or inverseagonistic effects may reside within 55 amnestic disorders due to a general medical condition, Sub the same chemical or biological compound. stance-induced persisting amnestic disorder, mild cognitive Taken into account the above mentioned (i) rare clinical or impairment disorder, other cognitive disorders; (iii) pain dis real effectiveness of psycho tropics, (ii) the governance of the orders; and (iv) Parkinson Disease. features and dysfunctions responsible—in a variable co-inci In a preferred embodiment, the first compound is admin dentally—for the clinical state of the mental disorders by D4 60 istered daily at least one day before administering said second (D4DR) and 2A serotonin receptor compound. (5-HT2A) antagonism and (iii) the fact that 5-HT2A antago Preferably, said second compound is characterized by the nism gives a des-inhibiting of the inhibitory effect of the physiological property of influencing positively the activity 5-HT2A receptor on (a) the 5-HT1A receptor stimulation by of the Central Nervous System. serotonin and on (b) the dopamine release in the mesocortical 65 The invention also relates to a method for preparing a systems, the present invention relates to the use of a com compound having a selective D4 and 5-HT2A antagonist, pound for the preparation of a medicament for treating a reverse agonist or partial agonist activity comprising the fol US 8,304,431 B2 5 6 lowing steps: (a) measuring the selective affinity of a test adjustment disorders, cognitive disorders, impulse control compound to the D4 receptor and selecting a compound that disorders, pervasive development, attention-deficit and dis has a pKi value equal to or greater than 8 towards the D4 ruptive behaviour disorders, substance-related disorders, per receptor in respect to all the other D receptors, and measuring Sonality disorders, psychological factors affecting medical the selective efficacy of the selected compound to the D4 conditions, malingering, antisocial behaviour, bereavement, receptor and selecting a compound which is a selective occupational, identity, phase of life, academic problem, prob antagonist, inverse agonist or partial agonist of the D4 recep lems related to abuse or neglect. tor; (b) measuring the selective affinity of a test compound to Mental disorders such as depression are commonly treated the 5-HT2A receptor and selecting a compound that has a pKi with serotonin re-uptake inhibitors. Unfortunately, however, value equal to or greater than 8 towards the 5-HT2A receptor 10 in respect to all the other 5HT receptors, and measuring the these compounds can give rise to side effects in use. More selective efficacy of the selected compound to the 5-HT2A over, a Substantial problem in most treatment of mental dis receptor and selecting a compound which is a selective orders is the non-response to selective serotonin re-uptake antagonist, inverse agonist or partial agonist of the 5-HT2A inhibitors (SSRIs). Also the onset of the therapeutic effect can receptor; (c) identifying a compound which is selected in (a) 15 be delayed undesirable. and (b), (d) preparing the compound identified in (c). A problem to be solved by the present invention is thus the The invention further also relates to a compound prepared provision of a more efficient therapy and efficient, highly by the described method. selective and efficacious medicaments for treating mental disorders. DETAILED DESCRIPTION OF THE INVENTION The inventors found that, for instance, the non-response to selective serotonin re-uptake inhibitors (SSRIs) in depression The present inventors surprisingly found that compounds may be declared by (partial) inhibition of the 5-HT1A stimu which have a high selective affinity towards the 5-HT2A lation via 5-HT2A stimulation. Des-inhibition thereof via receptor and which, at the same time have a high selective 5-HT2A antagonism seems to be an answer to this problem. affinity towards the dopamine-4 (D4) receptor show an 25 The present inventors found that a simultaneous or forego improved effect in treating underlying emotion dysregulation ing treatment with a compound having a high selective of mental disorders. 5-HT2A antagonist, inverse agonist or partial agonist activity, The compounds according to the invention may be chemi could lead to a greater response towards, for instance, SSRIs. cal or biological in nature, or may be chemically synthesised. However, not all compounds exhibiting 5-HT2A antagonism Preferably, the compounds of the invention are provided as a 30 are useful: competition between 5-HT2A stimulation via pharmaceutically acceptable salt. serotonin and 5-HT2A antagonism via the compound could One example of such a compound which has both a selec be responsible for the lack of more efficacy of compounds tive affinity for the 5-HT2A receptor with a pKi value equal to which have both a selective serotonin re-uptake inhibitory or higher than 8 towards the 5-HT2A receptor and less than 8 and 5-HT2A antagonist profile. Such as and nefa towards other 5HT receptors, and a selective affinity for the 35 Zodone. D4 receptor with a pKi value equal to or higher than 8 towards The present inventors further surprisingly found that a the D4 receptor and less than 8 towards other dopamine simultaneous or foregoing treatment with a compound having receptors is pipamperon. Pipamperon is the conventional a high selective D4 antagonist, inverse agonist or partial ago name given for the compound of the formula 1'-3-(p-Fluo nist activity in combination with a compound having a high robenzoyl)propyl-1,4'-bipiperidine-4-carboxamide. 40 selective 5-HT2A antagonist, inverse agonist or partial ago Pipamperon is also the active ingredient of for instance the nist activity could lead to a greater response towards, for commercially available Dipiperon (Janssen, Cilag B.V). instance, SSRIs, or any of the compounds listed in Table 6 or Further, the present inventors surprisingly found that the below. In addition, the inventors found that a combination dosage of active ingredient for pipamperon in treatment (in treatment provides less residual symptoms and more remis monotherapy as well as in combination therapy as described 45 sion relative to a monotherapy with these compounds. in more detail further) could be very low compared to con As such, in a combination treatment, the doses of the com ventionally used dosages. Preferred dosages which, accord pounds listed in Table 6 for treating patients with mental ing to the invention, have been shown to be effective for disorders may be decreased to about 10-90% of the conven treating these mental disorders, range between 5 and 15 mg tional dose, preferably to about 20-80%, or 30-70%, or per day or between 5 and 10 mg per day. More preferably, 50 40-60% or to about 50% of the conventional dose. Even if the dosages of 5,6,7,8,9, 10, 11, 12, 13, 14 or 15 mg per day are administered dose of the compound is decreased in the com used in treatment of the diseases of the invention. In conven bination therapy, the therapeutical effect may be sustained or tional pipamperon treatment, the active ingredient is available ameliorated relative to the conventional dose. The danger of in tablets of 40 mg per tablet or in Solutions of 2 mg per drop. side effects of a treatment with Such compounds can be Conventional usage of high doses ranging from 40 to 360 mg 55 decreased or minimized in the combination therapy of the is prescribed. For instance, for children up to the age of 14, invention. In this regard, the term conventional dose refers to doses corresponding with 2 to 6 mg per kg body weight are the dose used heretofor for a particular compound in treating conventionally prescribed. The high selective affinity of patients with a mental disorder, for instance, according to the pipamperon towards the 5-HT2A receptor and the D4 recep supplier's or physician's description or as listed in Table 6. tor is reflected in the low dosage which is needed for the 60 In this invention, the term “antagonist” refers to an inter treatment of the mental diseases listed below and also con action between chemicals in which one partially or com tributes to the efficacy of the treatment. pletely inhibits the effect of the other, in particular agents The mental disorders which can be treated using pipam having high affinity for a given receptor, but which do not peron in a mono therapy at Such low doses are for instance activate this receptor. anxiety disorders, eating disorders, premenstrual syndrome, 65 In this invention, the term “inverse agonist” refers to a Somatoform disorders, factitious disorders, dissociative dis ligand which produces an effect opposite to that of the agonist orders, sexual and gender identity disorders, sleep disorders, by occupying the same receptor. US 8,304,431 B2 7 8 In this invention, the term "agonist' relates to an agent pipamperon will provide for less side effects which otherwise which both binds to a receptor and has an intrinsic effect. result from simultaneous stimulation of other receptors. In this invention, the term "partial agonist' relates to an Therefore, and according to preferred embodiments, useful agent with lower intrinsic activity than a full agonist, and compounds according to the invention not only have a selec which produces a lower maximum effect. 5 tive 5-HT2A and/or D4 affinity but also a low affinity for other The present inventors found that a compound which binds receptors such as the adrenergic and histamine receptors. to the 5-HT2A receptor with a pKi of at least 8 but for which The low dosage which can be used in pipamperon treat the binding affinity, i.e. pKi, towards other 5HT receptors is ment, as already described earlier, contributes to the high less than 8 in combination with a high selective affinity for the selective affinity of the compound towards the 5-HT2A D4 receptor, i.e. which bind to the D4 receptor with a pKi of 10 receptor and the D4 receptor and therefore also to the efficacy at least 8 but for which the binding affinity, i.e. pKi, towards of the treatment. other dopamine receptors is less than 8 also show Such an The mental diseases or disorders characterized by an improved effect in treatment. These effects, i.e. D4 antago underlying emotion dysregulation can be grouped into Sub nism, inverse agonism or partial agonism and 5-HT2A classes as follows: (i) the non-cognitive mental disorders antagonism, inverse agonism or partial agonism, may reside 15 comprising mood disorders, anxiety disorders, psychotic dis in the same compound. orders, eating disorders, premenstrual syndrome, Somato The term “other 5HT receptors' as used herein relate to for form disorders (excluding pain disorders), factitious disor instance 5-HT1 receptors (e.g. 5-HT1A, 5-HT1B, 5-HT1D, ders, dissociative disorders, sexual and gender identity 5-HT1E, 5-HT1F), 5-HT2B, 5-HT2C, 5-HT6 (rat) and disorders, sleep disorders, adjustment disorders, impulse 5-HT7 (rat). control disorders, pervasive development disorders, atten By the expression “selective affinity for the 5-HT2A recep tion-deficit disorders, disruptive behaviour disorders, sub tor” is meant that the receptor has a higher affinity for the stance-related disorders, personality disorders, psychological 5-HT2A receptor than for other 5-HT receptors. factors affecting medical conditions, malingering, antisocial The expression “selective affinity for the D4 receptor behaviour, bereavement, occupational problems, identity means that the receptor has a higher affinity for the dopamine 25 problem, phase of life problem, academic problem and prob D4 receptor than for other dopamine receptors. lems related to abuse or neglect; (ii) cognitive diseases com The term “other dopamine receptors' are, for instance, D1, prising delirium, Alzheimer Disease, Substance-related per D2 and D3 dopamine receptors. sisting dementia, Vascular dementia, dementia due to HIV pKi values of test compounds for dopamine receptors as disease, dementia due to head trauma, dementia due to Par well as 5-HT2A receptors can be measured using commonly 30 kinson Disease, dementia due to Huntington Disease, demen known assays. tia due to Pick Disease, dementia due to Creutzfedt-Jacob Compounds which have a selective affinity for the D4 Disease, amnestic disorders due to a general medical condi receptor preferably have a pKi value equal to or higher than 8 tion, Substance-induced persisting amnestic disorder, mild towards the D4 receptor and less than 8 towards other dopam cognitive impairment disorder, other cognitive disorders; (iii) ine receptors. 35 the pain disorders; and (iv) Parkinson Disease. In Table 5, this Preferably, the compounds of the invention which have a classification has been used for Summarizing the diseases and selective affinity for the 5-HT2A receptor (or the D4 recep disorders relative to known psychotropics. In Table 6, an tor), are compounds which have a pKi value equal to or higher overview of pharmacological grouping is provided, indicat than 8 towards the 5-HT2A receptor and the D4 receptor, and ing the pharmalogical profile numbering, the pharmalogical less than 8 towards other 5-HT receptors or dopamine recep 40 profile, the main disease or disorderindication(s), the name of tors, respectively, as can be measured, for instance by meth the compound, the dose range, and the company producing or ods known in the art. For instance, the “NIMH Psychoactive selling said compound. Drug Screening Program (PDSP)' K, database (http://kidb These diseases and their diagnosis are very clearly defined .cwru.edu/nimh/5htp.php), is a unique resource in the public in the “Diagnostic and Statistical Manual of Mental Disorders domain which provides information on the abilities of drugs 45 (DSM-IV)' published by the American Psychiatric Associa to interact with an expanding number of molecular targets. tion. This manual sets forth diagnostic criteria, descriptions The PDSP K database serves as a data warehouse for pub and other information to guide the classification and diagno lished and internally-derived pKi, or affinity, values for a sis of mental disorders and is commonly used in the field of large number of drugs and drug candidates at an expanding neuropsychiatry. It is for instance available on the internet number of G-protein coupled receptors, ion channels, trans 50 under: porters and enzymes. The PDSP internet site also provides for http://www.behavenet.com/capsules/disorders/dsmatr.htm. commonly used protocols and assays for measuring pKi Val The expression “non-cognitive diseases or disorders' used ues of 5-HT and dopamine receptors. in some of the embodiments of the invention comprises the A preferred example of a compound which has both a following group of diseases or disorders: mood disorders, selective affinity for the 5-HT2A receptor with a pKi value 55 anxiety disorders, psychotic disorders, eating disorders, pre equal to or higher than 8 towards the 5-HT2A receptor and menstrual syndrome, Somatoform disorders (excluding pain less than 8 towards other 5-HT receptors, and a selective disorders), factitious disorders, dissociative disorders, sexual affinity for the D4 receptor with a pKi value equal to or higher and gender identity disorders, sleep disorders, adjustment than 8 towards the D4 receptor and less than 8 towards other disorders, impulse control disorders, pervasive development Dopamine receptors and which is therefore useful in a com 60 disorders, attention-deficit disorders, disruptive behaviour bination therapy is pipamperon. disorders, Substance-related disorders, personality disorders, Table 1 illustrates the selective affinity of for instance psychological factors affecting medical conditions, malinger pipamperon for the 5-HT2A and for the D4 receptor. In addi ing, antisocial behaviour, bereavement, occupational prob tion, Table 1 also illustrates the low or absence of affinity of lems, identity problem, phase of life problem, academic prob pipamperon for other receptors such as the adrenergic recep 65 lem and problems related to abuse or neglect. tors Alpha 1A, Alpha 2A, Alpha 2B, Alpha 2C, Beta 1, Beta 2. In other embodiments of the invention, the mental diseases and the histamine receptor H1. As such, treating patients with or disorders that are characterized by an underlying emotion US 8,304,431 B2 9 10 dysregulation belong to the group of pain disorders. For memories for more distant events and progresses over the instance, the combination therapy with pipamperon is espe course of five to ten years to a profound intellectual decline cially advantageous for management of acute pain in diseases characterized by dementia and personal helplessness. The Such as, but not limited to, musculoskeletal diseases, rheuma disease is marked histologically by the degeneration of brain toid arthritis, osteoarthritis and ankylosing spondylitis. For 5 neurons especially in the cerebral cortex and by the presence the classification of pain disorders, reference is also made to of neurofibrillary tangles and plaques containing beta-amy the DSM-IV where these disorders are clearly described in loid. Because dopamine receptor D4 (DRD4) antagonism can the section of somatoform disorders by way of internationally inhibit the behavioral disturbances—merely aggression and accepted diagnostic criteria. confusion—caused by the degeneration of dopamine D2 In other embodiments of the invention, the 5-HT2A recep 10 receptors (Esiri, M. M., The basis for behavioural distur tor and/or Dopamine-4 receptorantagonist, inverse agonist or bances in dementia, J. Neurol. Neurosurg. Psychiatry, 1996; partial agonist (e.g. pipamperon) is used in treatment of 61(2):127-130.2) accompanied with Alzheimer disease and patients having neuro-degenerative diseases or disorders, or 5-HT2A antagonism has an important boosting effect related cognitive diseases or disorders. The diseases or disor towards the effect of cholinesterase inhibitors such as used in ders of the present invention are characterized by an under- 15 the treatment by facilitating the affected dopamine release in lying degeneration of the Central Nervous System (CNS), the mesocortical dopamine pathways, a high selective D475 preferably selected from the group consisting of, but not HT2A-antagonist would be a more preferable compound to limited to, neurodegenerative diseases such as Parkinson Dis combine with a cholinesterase inhibitor since this avoids the ease, and in other embodiments of the invention, selected counteracting effect of the in the art used SDAs on the cog from the group of (related) cognitive diseases or disorders nitive functioning by its dopamine receptor D2-antagonism. Such as Alzheimer Disease. These diseases and their diagnoses are very clearly defined For instance, Parkinson Disease, which is a chronic pro in the “International Statistical Classification of Diseases gressive nervous disease chiefly of later life, is linked to and Related Health Problems, 1989 Revision, Geneva, World decreased dopamine production in the Substantia nigra and is Health Organization, 1992 (ICD-10). This manual sets forth marked by tremorand weakness of resting muscles and by a 25 diagnostic criteria, descriptions and other information to shuffling gait. Dopamine agonists and even levodopa, widely guide the classification and diagnosis of neurodegenerative used in Parkinson Disease, gives via a dopamine D4 receptor disorders and is commonly used in the field of neurology. stimulation psychiatric manifestations. The induced release According to the ICD-10 classification, the cognitive disor of serotonin acts via 5-HT2A stimulation as a “brake' on ders are classified under several classes of disorders, i.e. dopamine release (Young B. K., Camicioli R. Ganzini L., 30 dispersed under categories F00 to F19 (see above: respective Neuropsychiatric adverse effects of antiparkinsonian drugs. classification between parentheses). Following the DSM Characteristics, evaluation and treatment. Drugs Aging. classification, however, they are grouped in one class of dis 1997 May: 10(5):367-83). Because of the need of specific D4 eases or disorders. and 5-HT2A antagonism in the treatment of Parkinson Dis The terms “treatment”, “treating, and the like, as used ease with dopamine agonists and even levodopa, it seems 35 herein include amelioration or elimination of a developed reasonable to combine with a compound with a high selective mental disease or condition once it has been established or D4 and 5-HT2A antagonism i.e. having merely no activity alleviation of the characteristic symptoms of such disease or towards the other receptors especially the D2 receptor condition. As used herein these terms a so encompass, because of the primary need of the relieve of the excessive depending on the condition of the patient, preventing the burden of remaining dopaminergic neurons. Therefore, the 40 onset of a disease or condition or of symptoms associated use of the so-called atypical anti-psychotics or serotonin with a disease or condition, including reducing the severity of dopamine antagonists (SDAS) is absolutely contra-indicated a disease or condition or symptoms associated therewith prior since their high affinity for the D2 receptor. Even the use of to affliction with said disease or condition. Such prevention or serotonin releasing compounds such as SSRIs in the absence reduction prior to affliction refers to administration of the of an effective 5-HT2A antagonism are contra-productive 45 compound or composition of the invention to a patient that is towards the Parkinson Disease symptoms although many Par not at the time of administration afflicted with the disease or kinson patients are in need for an antidepressant since major condition. “Preventing also encompasses preventing the depression is a very common and disabling condition in this recurrence or relapse-prevention of a disease or condition or kind of patients. of symptoms associated therewith, for instance after a period The expression “(related) cognitive diseases or disorders' 50 of improvement. It should be clear that mental conditions according to the invention comprises, the following group of may be responsible for physical complaints. In this respect, diseases or disorders: delirium (F05), dementia (such as the term “treating also includes prevention of a physical Alzheimer Disease (F00), vascular dementia (F01), dementia disease or condition or amelioration or elimination of the due to other general medical conditions (HIV disease (F02.4), developed physical disease or condition once it has been head trauma (F06.8), Parkinson Disease (F02.3), Huntington 55 established or alleviation of the characteristic symptoms of Disease (F02.2), Pick Disease (F02.0), Creutzfeldt-Jacob Such conditions. Disease (F02.1) and other (F02.8)), substance-induced per As used herein, the term “medicament also encompasses sisting dementia (F1X.6)), amnestic disorders due to a general the terms “drug”, “therapeutic”, “potion' or other terms medical condition (F06.8) or a Substance-induced persisting which are used in the field of medicine to indicate a prepara amnestic disorder (F1X.6), mild cognitive impairment disor- 60 tion with therapeutic or prophylactic effect. der (F06.7) and other cognitive disorders (F04). The above The present inventors not only found that the selective list of diseases is provided by way of example and is not 5-HT2A and D4 antagonists, inverse agonists or partial ago intended to limit the invention. nists have an effect in augmenting the therapeutic effect or in For instance, Alzheimer Disease is a degenerative brain providing a faster onset of the therapeutic effect of a diversity disease of unknown cause that is the most common form of 65 of other pharmaceutical compounds, i.e. also named 'second dementia. Alzheimer Disease usually starts in late middle age compounds' in the present invention, in the treatment of or in old age as a memory loss for recent events spreading to specific diseases or disorders. A few examples of other phar US 8,304,431 B2 11 12 maceutical compounds whose effects are augmented or second compound. Preferably, the 5-HT2A and D4 antago where the onset of the effect is fastened upon simultaneous or nist, inverse agonist or partial agonist (e.g. pipamperon) or the fore-going treatment with a selective 5-HT2A and D4 antago composition compressing both elements is administered for nist, preferably pipamperon in a low dose, are nor-epineph at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days prior to the admin rine re-uptake inhibitors, neuroleptic agents, dopamine istration of the second compound. Preferably, the 5-HT2A antagonists, or compounds used for treating or alleviating and D4 antagonist, inverse agonist or partial agonist (e.g. musculoskeletal diseases or disorders. A further list of other pipamperon) or the composition comprising both elements is pharmaceutical compounds or second compounds useful administered for at least 2, 3, 4 or 5 weeks prior to the according to the invention is provided in Table 5. It should be administration of the second compound, or even for at least 1, clear, given the general applicable character of the invention, 10 that this list of other pharmaceutical compounds is very brief 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months prior to the admin and that the invention should not be restricted to the ones istration of the second compound. exemplified herein. It should be clear that in the present According to a preferred embodiment of the invention, the invention, pipamperon is never to be seen as a 'second com above described compounds or the composition comprising pound'. 15 both elements having a 5-HT2A and D4 antagonist, inverse According to the invention, it thus has been found that the agonist or partial agonist activity are useful for augmenting compounds having a selective 5-HT2A and D4 antagonist, the therapeutic effect of citalopram or for providing a faster inverse agonist or partia agonist activity as described above onset of the therapeutic effect of citalopram. are useful for augmenting the therapeutic effect of a second Citalopram or citalopram hydrobromide is a selective sero compound on a disease. tonin (5-hydroxytryptamine/5-HT) re-uptake inhibitor According to another embodiment of the invention, it has (SSRI) and is the conventional name given for the compound also been found that the compounds having a selective of the formula (RS)-1-3-(dimethylamino)propyl-1-(p-fluo 5-HT2A and D4 antagonist, inverse agonist or partial agonist rophenyl)-5-phthalancarbonitrile hydro-bromide. activity as described above are useful for providing a faster According to an embodiment, a daily dose of active ingre onset of the therapeutic effect of a second compound on a 25 dient of SSRI, preferably citalopram, ranges between 10 and disease. 40 mg per day. Preferably, daily doses of active ingredient From the above it should be clear that the selective 5-HT2A ranging between 20 and 30 mg per day are administered. and D4 antagonist, inverse agonist or partial agonist is also More preferably, a daily dose of 10, 15, 20, 25, 30, 35 or 40 named the first compound in the embodiments of the inven mg per day is administered. tion. 30 According to another preferred embodiment of the inven According to the invention, when the 5-HT2A and D4 tion, the above described compounds or the composition antagonist, inverse agonist or partial agonist activity reside in comprising both elements having a 5-HT2A and D4 antago separate compounds, the term "composition may be used. nist, inverse agonist or partial agonist activity are useful for Compositions of the invention comprise a first element hav augmenting the therapeutic effect of fluvoxamine or for pro ing (i) a selective affinity for the D4 receptor with a pKi value 35 viding a faster onset of the therapeutic effect of fluvoxamine. equal to or higher than 8towards the D4 receptor and less than Fluvoxamine or fluvoxamine maleate (luvox, fevarin) is a 8 towards other dopamine receptors, and a second element selective serotonin (5-HT) reuptake inhibitor (SSRI) belong having (ii) a selective affinity for the 5-HT2A receptor with a ing to a new chemical series, the 2-aminoethyl oxime ethers pKi value equal to or higher than 8 towards the 5-HT2A of aralkylketones. It is chemically unrelated to other SSRIs receptor and less than 8 towards other 5-HT receptors. 40 and . It is chemically designated as 5-methoxy The expression “the 5-HT2A and D4 antagonist, inverse 4'-(trifluoromethyl)Valerophenone (E)-O-(2-aminoethyl) agonist or partial agonist’ is used herein to indicate a single Oxime maleate (1:1). compound having both activities or to indicate the composi According to an embodiment, a daily dose of active ingre tion comprising the activities in separate elements. dient of fluvoxamine maleate ranges between 100 and 300 mg It should be clear that when, in the present invention, a 45 per day. Preferably, daily doses of active ingredient ranging composition of separate elements is used instead of a single between 150 and 200 mg per day are administered. More compound, this composition of separate elements may be preferably, a daily dose of 100, 150, 200, 250 or 300 mg per used in combination with another, i.e. a second, compound to day is administered. augment the therapeutic effect of the other, i.e. the second, According to a preferred embodiment of the invention, the compound on the same or another disease. 50 above described compounds or the composition comprising When the 5-HT2A and D4 antagonist, inverse agonist or both elements having a 5-HT2A and D4 antagonist, inverse partial agonist or the composition comprising both elements agonist or partial agonist activity are useful for augmenting and the second compound are administered simultaneously, the therapeutic effect of seiegiline or for providing a faster the compounds or active ingredients may be present in a onset of the therapeutic effect of selegiline. single pharmaceutical composition or formulation. Alterna 55 Selegiline or L-deprenyl or phenylisopropyl methylpropy tively the compounds or active ingredients are administered nyl amine is a monoamine oxidase B inhibitor (MAO-B in separate pharmaceutical compositions or formulations for inhibitor) and is the conventional name given for the com simultaneous or separate use. The invention thus also relates pound of the formula (R)-(-)-N, C-dimethyl-N-(2-propynyl) to pharmaceutical compositions comprising pipamperon and phenethylamine-HC1. a second compound of the invention and to the uses of these 60 According to an embodiment, a daily dose of active ingre pharmaceutical compositions. dient of MAO-B inhibitor, preferably selegiline, ranges When the 5-HT2A and D4 antagonist, inverse agonist or between 5 and 60 mg per day. Preferably, daily doses of active partial agonist or the composition comprising both elements ingredient ranging between 20 and 40 mg per day are admin of the invention are administered prior to the second com istered. More preferably, a daily dose of 10, 15, 20, 25, 30, 35 pound as defined, the 5-HT2A and D4 antagonist, inverse 65 or 40 mg per day is administered. agonist or partial agonist or the composition comprising both Most of the second compounds herein described are known elements is administered at least during 1 day prior to said in the art and may be used in doses according to the Supplier's US 8,304,431 B2 13 14 or physician's prescription, or may be used according to the active compounds and one that has no detrimental side specific embodiments described herein. effects or toxicity under the conditions of use. Also encompassed by the invention are pro-drugs to these The following formulations for oral, aerosol, parenteral, second compounds or active metabolites of these compounds. Subcutaneous, intravenous, intramuscular, interperitoneal, For instance, for risperidone it is known that, among other rectal, and vaginal administration are merely exemplary and products, bio transformation in the liver produces 9-hydrox are in no way limiting. Overall, the requirements for effective yrisperidone, which is of the same pharmacological activity pharmaceutical carriers for parenteral compositions are well and intensity as parent risperidone. Therefore, also 9-hydrox known to those of ordinary skill in the art. See Pharmaceutics yrisperidone, naturally produced or chemically synthesized and Pharmacy Practice, J.B. Lippincott Company, Philadel 10 phia, Pa., Banker and Chalmers, eds., pages 238-250, (1982), may be used in the methods and uses according to the inven and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., tion. pages 622-630 (1986). Topical formulations, including those The term “active metabolite' as used herein relates to a that are useful for transdermal drug release, are well-known therapeutically active compound produced by the metabo to those of skill in the art and are suitable in the context of the lism of a parent drug. Drugs administered to treat diseases are 15 present invention for application to skin. usually transformed (metabolized) within the body into a Formulations suitable for oral administration require extra variety of related chemical forms (metabolites), some of considerations considering the nature of the compounds and which may have therapeutic activity (an active metabolite). the possible breakdown thereof if such compounds are The present invention also encompasses the use of these administered orally without protecting them from the diges second compounds, administered in the form of a pharma tive secretions of the gastrointestinal tract. Such a formula ceutically acceptable salt in admixture with a suitable phar tion can consist of (a) liquid solutions. Such as an effective maceutically acceptable excipient. amount of the compound dissolved in diluents, such as water, To prepare the pharmaceutical compositions, comprising saline, or orange juice; (b) capsules, Sachets, tablets, loZ the compounds or the combination of the first and second enges, and troches, each containing a predetermined amount compound described herein, an effective amount of the active 25 of the active ingredient, as Solids or granules; (c) powders; (d) ingredients, in acid or base addition salt form or base form, is Suspensions in an appropriate liquid; and (e) Suitable emul combined in admixture with a pharmaceutically acceptable sions. Liquid formulations may include diluents, such as carrier, which can take a wide variety of forms depending on water and , for example, ethanol, benzyl alcohol, and the form of preparation desired for administration. These the polyethylene alcohols, either with or without the addition pharmaceutical compositions are desirably in unitary dosage 30 of a pharmaceutically acceptable Surfactant, Suspending form Suitable, for administration orally, nasal, rectally, per agent, or emulsifying agent. Capsule forms can be of the cutaneously, transdermally, by parenteral, intramuscular, ordinary hard- or soft-shelled gelatin type containing, for intravascular injection or intrathecal administration. For example, Surfactants, lubricants, and inert fillers, such as example, in preparing the compositions in oral dosage form, lactose, Sucrose, calcium phosphate, and corn starch. Tablet any of the usual pharmaceutical media may be employed, 35 forms can include one or more of lactose. Sucrose, mannitol, Such as, for example, water, glycols, oils, alcohols and the like corn starch, potato starch, alginic acid, microcrystalline cel in the case of oral liquid preparations such as Suspensions, lulose, acacia, gelatin, guar gum, colloidal silicon dioxide, syrups, elixirs and solutions; or solid carriers such as starches, croScarmellose Sodium, talc, magnesium Stearate, calcium Sugars, kaolin, lubricants, binders, disintegrating agents and Stearate, Zinc Stearate, Stearic acid, and other excipients, colo the like in the case of powders, pills, capsules and tablets. 40 rants, diluents, buffering agents, disintegrating agents, moist Because of their ease in administration, tablets and capsules ening agents, preservatives, flavoring agents, and pharmaco represent the most advantageous oral dosage unit form, in logically compatible excipients. Lozenge forms can comprise which case solid pharmaceutical carriers are obviously the active ingredient in a flavor, usually Sucrose and acacia or employed. For parenteral compositions, the carrier will usu tragacanth, as well as pastilles comprising the active ingredi ally comprise sterile water, at least in large part, though other 45 ent in an inert base. Such as gelatin and glycerin, or Sucrose ingredients, for example, to aid solubility, may be included. and acacia, emulsions, gels, and the like containing, in addi The pharmaceutical compounds for treatment are intended tion to the active ingredient, such excipients as are known in for parenteral, topical, oral or local administration and gen the art. erally comprise a pharmaceutically acceptable carrier and an The compounds of the present invention, alone or in com amount of the active ingredient sufficient to reverse or prevent 50 bination with other Suitable components, can be made into the bad effects of mental disorders. The carrier may be any of aerosol formulations to be administered via inhalation. For those conventionally used and is limited only by chemico aerosol administration, the compounds are preferably Sup physical considerations, such as solubility and lack of reac plied in finely divided form along with a Surfactant and pro tivity with the compound, and by the route of administration. pellant. Typical percentages of compounds are 0.01%-20% Examples of pharmaceutically acceptable acid addition 55 by weight, preferably 1%-10%. The surfactant must, of salts for use in the present inventive pharmaceutical compo course, be nontoxic, and preferably soluble in the propellant. sition include those derived from mineral acids, such as Representative of such agents are the esters or partial esters of hydrochloric, hydrobromic, phosphoric, metaphosphoric, fatty acids containing from 6 to 22 carbon atoms, such as nitric and Sulfuric acids, and organic acids, Such as tartaric, caproic, octanoic, lauric, palmitic, Stearic; linoleic, linolenic, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, glu 60 olesteric and oleic acids with an aliphatic polyhydric alcohol conic, Succinic, p-toluenesulphonic acids, and arylsulphonic, or its cyclic anhydride. Mixed esters. Such as mixed or natural for example. glycerides may be employed. The Surfactant may constitute The pharmaceutically acceptable excipients described 0.1%-20% by weight of the compounds, preferably 0.25-5%. herein, for example, vehicles, adjuvants, carriers or diluents, The balance of the compounds is ordinarily propellant. A are well-known to those who are skilled in the art and are 65 carrier can also be included as desired, e.g., lecithin for intra readily available to the public. It is preferred that the pharma nasal delivery. These aerosol formulations can be placed into ceutically acceptable carrier be one that is chemically inert to acceptable pressurized propellants, such as dichlorodifluo US 8,304,431 B2 15 16 romethane, propane, nitrogen, and the like. They also may be therapeutic effect or to provide a faster onset of the therapeu formulated as pharmaceuticals for non-pressured prepara tic effect of said 5-HT (serotonin) reuptake enhancer com tions, such as in a nebulizer or an atomizer. Such spray for pound, further characterized in that pipamperon is to be mulations may be used to spray mucosa. administered to a patient in a daily dose ranging between 5 It will be understood that, apart from daily doses, the com- 5 and 15 mg of the active ingredient. pounds can be administered by other schedules. For instance, The present invention thus relates to the use of pipamperon the present invention also contemplates depot injection, in or a pharmaceutically acceptable salt thereof for the prepara which a long acting form of the active compound is injected tion of a medicament for treating the underlying emotion into the body, such as the muscles. From there the active dysregulation of pain disorders, characterized in that pipam compound slowly enters the rest of the body, so one injection 10 peron or said pharmaceutically acceptable salt thereof is can last from 1 to 4 weeks or even multiple months. Other administered simultaneously with, separate from or prior to form of dosage administrations relate to “once-a-week pills, the administration of a 5-HT (serotonin) reuptake enhancer in which the ingredient is slowly released over a period of a compound to augment the therapeutic effect or to provide a week, and slow-release patches, e.g. a CDS (Continuous faster onset of the therapeutic effect of said 5-HT (serotonin) Delivery System), or Once-a-Day Transdermal Patches. 15 reuptake enhancer compound, further characterized in that According to a further embodiment, the invention also pipamperon is to be administered to a patient in a daily dose relates to a method for preparing a compound or composition ranging between 5 and 15 mg of the active ingredient. having a selective D4 and 5-HT2A antagonist, reverseagonist According to a preferred embodiment, the invention relates or partial agonist. The invention also relates to the compounds to the uses as described above, wherein said 5-HT (serotonin) prepared by the claimed method, with the proviso that said 20 reuptake enhancer compound is tianeptine or a pro-drug oran compound is not an already known compound, such as active metabolite thereof, or a pharmaceutically acceptable pipamperon. salt thereof. Preferably, tianeptine is to be administered in a It should be clear that the compounds and compositions daily dose ranging between 25 and 50 mg of the active ingre described herein are useful for treating any patient in need dient. thereof. As used herein the term “patient' is not restricted to 25 The inventiona' So relates to a pharmaceutical composition humans but also to other mammals, for instance, domestic comprising (a) pipamperon, and (b) a 5-HT (serotonin) animals which may also Suffer from any form of a mental reuptake enhancer, preferably tianeptine or a pro-drug or an disease or disorder described herein. active metabolite thereof, or a pharmaceutically acceptable The second compounds of the invention can be further salt thereof, as a combined preparation for simultaneous, grouped according to their pharmacological profile, which is 30 separate or sequential use for treating the underlying emotion summarized in Table 6. dysregulation of a mental disease or disorder which is chosen The present invention is now described in more detail by from the group of diseases or disorders consisting of mood the following embodiments. The compounds belonging to disorders, anxiety disorders, eating disorders, premenstrual different pharmacological profiles can be further grouped syndrome, Somatoform disorders (excluding pain disorders), according to their action on the same pathway or system as 35 factitious disorders, dissociative disorders, sexual and gender follows. identity disorders, sleep disorders, adjustment disorders, 1: Combination Therapy with a 5-HT (Serotonin) Reuptake impulse control disorders, Substance related disorder, person Enhancer ality disorder, antisocial behaviour, bereavement, occupa The mental disorders which can be treated using com tional problem, problems related to abuse or neglect and pain pounds having a high selective affinity for the 5-HT2A and 40 disorders. D4 receptor, for instance pipamperon, in a combination A pharmaceutical composition as described above wherein therapy with a 5-HT (serotonin) reuptake enhancer, are cho pipamperon is provided in a unitary dose of between 5 and 15 Sen from the group of diseases or disorders consisting of mg of the active ingredient and wherein said 5-HT (serotonin) mood disorders, anxiety disorders, eating disorders, premen reuptake enhancer is tianeptine, preferably provided in a uni strual syndrome, Somatoform disorders (excluding pain dis- 45 tary dose of between 25 and 50 mg of the active ingredient. orders), factitious disorders, dissociative disorders, sexual 2: Combination Therapy with a 5-HT1 Autoreceptor Agonist and gender identity disorders, sleep disorders, adjustment The mental disorders which can be treated using com disorders, impulse control disorders, Substance related disor pounds having a high selective affinity for the 5-HT2A and der, personality disorders, antisocial behaviour, bereavement, D4 receptor, for instance pipamperon, in a combination occupational problem, problems related to abuse or neglect 50 therapy with a 5-HT1 autoreceptor agonist, are chosen from and pain disorders. the group of diseases or disorders consisting of mood disor The present invention thus relates to the use of pipamperon ders, anxiety disorders, eating disorders, premenstrual Syn or a pharmaceutically acceptable salt thereof for the prepara drome. Somatoform disorders (excluding pain disorders), fac tion of a medicament for treating the underlying emotion titious disorders, dissociative disorders, sexual and gender dysregulation of a non-cognitive mental disease or disorder 55 identity disorders, sleep disorders, adjustment disorders, selected from the group of diseases or disorders consisting of impulse control disorders, Substance related disorder, person mood disorders, anxiety disorders, eating disorders, premen ality disorders, antisocial behaviour, bereavement, occupa strual syndrome, Somatoform disorders (excluding pain dis tional problem, problems related to abuse or neglect and pain orders), factitious disorders, dissociative disorders, sexual disorders. and gender identity disorders, sleep disorders, adjustment 60 The present invention thus relates to the use of pipamperon disorders, impulse control disorders, Substance related disor or a pharmaceutically acceptable salt thereof for the prepara der, personality disorders, antisocial behaviour, bereavement, tion of a medicament for treating the underlying emotion occupational problem and problems related to abuse or dysregulation of a non-cognitive mental disease or disorder neglect, characterized in that pipamperon or said pharmaceu selected from the group of diseases or disorders consisting of tically acceptable salt thereof is administered simultaneously 65 mood disorders, anxiety disorders, eating disorders, premen with, separate from or prior to the administration of a 5-HT strual syndrome, Somatoform disorders (excluding pain dis (serotonin) reuptake enhancer compound to augment the orders), factitious disorders, dissociative disorders, sexual US 8,304,431 B2 17 18 and gender identity disorders, sleep disorders, adjustment menstrual syndrome, Somatoform disorders (excluding pain disorders, impulse control disorders, Substance related disor disorders), factitious disorders, dissociative disorders, sexual der, personality disorders, antisocial behaviour, bereavement, and gender disorders, sleep disorders, adjustment disorders, occupational problem and problems related to abuse or impulse control disorders, attention-deficit disorders, Sub neglect, characterized in that pipamperon or said pharmaceu stance-related disorder, personality disorders, antisocial tically acceptable salt thereof is administered simultaneously behaviour, bereavement, occupational problem and problems with, separate from or prior to the administration of a 5-HT1 related to abuse or neglect, characterized in that pipamperon autoreceptor agonist compound to augment the therapeutic or said pharmaceutically acceptable salt thereof is adminis effect or to provide a faster onset of the therapeutic effect of tered simultaneously with, separate from or prior to the said 5-HT1 autoreceptor agonist compound, further charac 10 administration of a 5-HT1A (serotonin 1A receptor) agonist terized in that pipamperon is to be administered to a patient in compound to augment the therapeutic effect or to provide a a daily dose ranging between 5 and 15 mg of the active faster onset of the therapeutic effect of said 5-HT1A (seroto ingredient. nin 1A receptor) agonist compound, further characterized in The present invention thus relates to the use of pipamperon that pipamperon is to be administered to a patient in a daily or a pharmaceutically acceptable salt thereof for the prepara 15 dose ranging between 5 and 15 mg of the active ingredient. tion of a medicament for treating the underlying emotion The present invention further also relates to the use of dysregulation of pain disorders, characterized in that pipam pipamperon or a pharmaceutically acceptable salt thereof for peron or said pharmaceutically acceptable salt thereof is the preparation of a medicament for treating the underlying administered simultaneously with, separate from or prior to emotion dysregulation of pain disorders, characterized in that the administration of a 5-HT1 autoreceptor agonist com pipamperon or said pharmaceutically acceptable salt thereof pound to augment the therapeutic effect or to provide a faster is administered simultaneously with, separate from or prior to onset of the therapeutic effect of said 5-HT1 autoreceptor the administration of a 5-HT1A (serotonin 1A receptor) ago agonist compound, further characterized in that pipamperon nist compound to augment the therapeutic effect or to provide is to be administered to a patient in a daily dose ranging a faster onset of the therapeutic effect of said 5-HT1A (sero between 5 and 15 mg of the active ingredient. 25 tonin 1A receptor) agonist compound, further characterized According to a preferred embodiment, the invention relates in that pipamperon is to be administered to a patient in a daily to the uses as described above, wherein said 5-HT1 autore dose ranging between 5 and 15 mg of the active ingredient. ceptor agonist compound is or a pro-drug or an According to a preferred embodiment, the invention relates active metabolite thereof, or a pharmaceutically acceptable to the uses as described above, wherein said 5-HT1A (sero salt thereof. 30 tonin 1A receptor) agonist compound is chosen from the The invention also relates to a pharmaceutical composition group consisting of MN-305, , , VPI comprising (a) pipamperon, and (b) a 5-HT1 autoreceptor 013 (also known as OPC-14523), tandosprione, , agonist, preferably Sunepitron or a pro-drug or an active PRX-00023, metanospirone, , , flesi metabolite thereof, or a pharmaceutically acceptable salt noxan, EMD 68843, , (preferably con thereof, as a combined preparation for simultaneous, separate 35 trolled release formulation) and , preferably or sequential use for treating the underlying emotion dysregu Xaliproden, Sarizotan, gepirone, and bupropion lation of amental disease or disorder which is chosen from the (preferably controlled release formulation) or a pro-drug or group of diseases or disorders consisting of mood disorders, an active metabolite thereof, or a pharmaceutically accept anxiety disorders, eating disorders, premenstrual syndrome, able salt thereof. More preferably, said 5-HT1A (serotonin Somatoform disorders (excluding pain disorders), factitious 40 1A receptor)agonist is Xaliproden and is to be administered in disorders, dissociative disorders, sexual and gender identity a daily dose ranging between 1 and 2 mg of the active ingre disorders, sleep disorders, adjustment disorders, impulse dient. Even more preferably, said 5-HT1A (serotonin 1A control disorders, Substance related disorder, personality dis receptor) agonist is buproprion (controlled release formula order, antisocial behaviour, bereavement, occupational prob tion) and is to be administered in a daily dose ranging between lem, problems related to abuse or neglect and pain disorders. 45 150 and 450 mg of the active ingredient. Even more prefer 3: Combination Therapy with a 5-HT1A (Serotonin 1A ably, said 5-HT1A (serotonin 1A receptor) agonist is Receptor) Agonist Compound gepirone and is to be administered in a daily dose, ranging The mental disorders which can be treated using com between 20 and 80 mg of the active ingredient per day. pounds having a high selective affinity for the 5-HT2A and The invention also relates to a pharmaceutical composition D4 receptor, for instance pipamperon, in a combination 50 comprising (a) pipamperon, and (b) a 5-HT1A (serotonin 1A therapy with a 5-HT1A (serotonin 1A receptor) agonist com receptor) agonist, preferably chosen from the group consist pound, are chosen from the group of diseases or disorders ing of MN-305, Zalospirone, xaliproden, VPI-013 (also consisting of mood disorders, anxiety disorders, eating dis known as OPC-14523), tandosprione, sarizotan, PRX-00023, orders, premenstrual syndrome, Somatoform disorders (ex metanospirone, lesopitron, gepirone, fiesinoxan, EMD cluding pain disorders), factitious disorders, dissociative dis 55 68843, buspirone, bupropion (preferably controlled release orders, sexual and gender disorders, sleep disorders, formulation) and alnespirone, more preferably Xaliproden, adjustment disorders, impulse control disorders, attention sarizotan, gepirone, flesinoxan and bupropion (preferably deficit disorders, Substance-related disorder, personality dis controlled release formulation), or a pro-drug or an active orders, antisocial behaviour, bereavement, occupational metabolite thereof, or a pharmaceutically acceptable salt problem, problems related to abuse or neglect and pain dis 60 thereof, as a combined preparation for simultaneous, separate orders. or sequential use for treating the underlying emotion dysregu The present invention thus relates to the use of pipamperon lation of amental disease or disorder which is chosen from the or a pharmaceutically acceptable salt thereof for the prepara group of diseases or disorders consisting of mood disorders, tion of a medicament for treating the underlying emotion anxiety disorders, eating disorders, premenstrual syndrome, dysregulation of a non-cognitive mental disease or disorder 65 Somatoform disorders (excluding pain disorders), factitious selected from the group of diseases and disorders consisting disorders, dissociative disorders, sexual and gender disor of mood disorders, anxiety disorders, eating disorders, pre ders, sleep disorders, adjustment disorders, impulse control US 8,304,431 B2 19 20 disorders, attention-deficit disorders, Substance-related dis metabolite thereof, or a pharmaceutically acceptable salt order, personality disorders, antisocial behaviour, bereave thereof, as a combined preparation for simultaneous, separate ment, occupational problem, problems related to abuse or or sequential use for treating the underlying emotion dysregu neglect and pain disorders. lation of a non-cognitive mental disease or disorder which is The present invention also relates to a pharmaceutical com chosen from the group of diseases or disorders consisting of position as described above wherein pipamperon is provided mood disorders, anxiety disorders, eating disorders, premen in a unitary dose of between 5 and 15 mg of the active strual syndrome, Somatoform disorders (excluding pain dis ingredient and wherein said 5-HT1A (serotonin 1A receptor) orders), factitious disorders, dissociative disorders, sexual agonist is Xaliproden, preferably provided in a unitary dose of and gender disorders, adjustment disorders, impulse control between 1 and 2 mg of the active ingredient. 10 disorders, Substance-related disorder, personality disorders, The present invention also relates to a pharmaceutical com antisocial behaviour, bereavement, occupational problemand position as described above wherein pipamperon is provided problems related to abuse or neglect. in a unitary dose of between 5 and 15 mg of the active 5: Combination Therapy with a 5-HT1B (Serotonin 1B ingredient and wherein said 5-HT1A (serotonin 1A receptor) Receptor) Antagonist Compound agonist is buproprion (controlled release formulation), pref 15 The mental disorders which can be treated using com erably provided in a unitary dose of between 150 and 450 mg pounds having a high selective affinity for the 5-HT2A and of the active ingredient. D4 receptor, for instance pipamperon, in a combination The present invention also relates to a pharmaceutical com therapy with a 5-HT1B (serotonin 13 receptor) antagonist position as described above wherein pipamperon is provided compound, are chosen from the group of diseases or disorders in a unitary dose of between 5 and 15 mg of the active consisting of mood disorders, anxiety disorders, eating dis ingredient and wherein said 5-HT1A (serotonin 1A receptor) orders, premenstrual syndrome, Somatoform disorders (ex agonist is gepirone, preferably provided in a unitary dose of cluding pain disorders), factitious disorders, dissociative dis between 20 and 80 mg of the active ingredient. orders, sexual and gender disorders, sleep disorders, 4: Combination Therapy with a 5-HT1A (Serotonin 1A adjustment disorders, impulse control disorders, Substance Receptor) Antagonist Compound 25 related disorder, personality disorders, antisocial behaviour, The mental disorders which can be treated using com bereavement, occupational problem and problems related to pounds having a high selective affinity for the 5-HT2A and abuse or neglect. D4 receptor, for instance pipamperon, in a combination The present invention thus relates to the use of pipamperon therapy with a 5-HT1A (serotonin 1A receptor) antagonist or a pharmaceutically acceptable salt thereof for the prepara compound, are chosen from the group of diseases or disorders 30 tion of a medicament for treating the underlying emotion consisting of mood disorders, anxiety disorders, eating dis dysregulation of a non-cognitive mental disease or disorder orders, premenstrual syndrome, somatoform disorders (ex selected from the group of diseases and disorders consisting cluding pain disorders), factitious disorders, dissociative dis of mood disorders, anxiety disorders, eating disorders, pre orders, sexual and gender disorders, adjustment disorders, menstrual syndrome, Somatoform disorders (excluding pain impulse control disorders, Substance-related disorder, per 35 disorders), factitious disorders, dissociative disorders, sexual Sonality disorders, antisocial behaviour, bereavement, occu and gender disorders, sleep disorders, adjustment disorders, pational problem and problems related to abuse or neglect. impulse control disorders, Substance-related disorder, per The present invention thus relates to the use of pipamperon Sonality disorders, antisocial behaviour, bereavement, occu or a pharmaceutically acceptable salt thereof for the prepara pational problem and problems related to abuse or neglect, tion of a medicament for treating the underlying emotion 40 characterized in that pipamperon or said pharmaceutically dysregulation of a non-cognitive mental disease or disorder acceptable salt thereof is administered simultaneously with, selected from the group of diseases and disorders consisting separate from or prior to the administration of a 5-HT1B of mood disorders, anxiety disorders, eating disorders, pre antagonist compound to augment the therapeutic effect or to menstrual syndrome, Somatoform disorders (excluding pain provide a faster onset of the therapeutic effect of said 5-HT1B disorders), factitious disorders, dissociative disorders, sexual 45 antagonist compound, further characterized in that pipam and gender disorders, adjustment disorders, impulse control peron is to be administered to a patient in a daily dose ranging disorders, Substance-related disorder, personality disorders, between 5 and 15 mg of the active ingredient. antisocial behaviour, bereavement, occupational problemand According to a preferred embodiment, the invention relates problems related to abuse or neglect, characterized in that to the use as described above, wherein said 5-HT1Bantago pipamperon or said pharmaceutically acceptable salt thereof 50 nist compound is chosen from the group consisting of elza is administered simultaneously with, separate from or prior to sonan, AZD1134 and AR-A2, preferably , or a pro the administration of a 5-HT1A antagonist compound to aug drug or an active metabolite thereof, or a pharmaceutically ment the therapeutic effect or to provide a faster onset of the acceptable salt thereof. therapeutic effect of said 5-HT1A antagonist compound, fur The invention also relates to a pharmaceutical composition ther characterized in that pipamperon is to be administered to 55 comprising (a) pipamperon, and (b) a 5-HT1B antagonist, a patient in a daily dose ranging between 5 and 15 mg of the preferably chosen from the group consisting of elzasonan, active ingredient. AZD1134 and AR-A2, preferably elzasonan, or a pro-drug or According to a preferred embodiment, the invention relates an active metabolite thereof, or a pharmaceutically accept to the uses as described above, wherein said 5-HT1A antago able salt thereof, as a combined preparation for simultaneous, nist compound is chosen from the group consisting of robal 60 separate or sequential use for treating the underlying emotion Zotan tartrate hydrate and NAD299 or a pro-drug or an active dysregulation of a non-cognitive mental disease or disorder metabolite thereof, or a pharmaceutically acceptable salt which is chosen from the group of diseases or disorders thereof. consisting of mood disorders, anxiety disorders, eating dis The invention also relates to a pharmaceutical composition orders, premenstrual syndrome, Somatoform disorders (ex comprising (a) pipamperon, and (b) a 5-HT1A antagonist, 65 cluding pain disorders), factitious disorders, dissociative dis preferably chosen from the group consisting of orders, sexual and gender disorders, sleep disorders, tartrate hydrate and NAD299, or a pro-drug or an active adjustment disorders, impulse control disorders, Substance US 8,304,431 B2 21 22 related disorder, personality disorders, antisocial behaviour, ders, dissociative disorders, sexual and gender disorders, bereavement, occupational problem and problems related to sleep disorders, adjustment disorders, impulse control disor abuse or neglect. ders, Substance-related disorder, personality disorders, anti 6: Combination Therapy with a 5-HT2B (Serotonin 2B Social behaviour, bereavement, occupational problem, prob Receptor) Antagonist Compound lems related to abuse or neglect and pain disorders. The mental disorders which can be treated using com A pharmaceutical composition as described above wherein pounds having a high selective affinity for the 5-HT2A and pipamperon is provided in a unitary dose of between 5 and 15 D4 receptor, for instance pipamperon, in a combination mg of the active ingredient and wherein said 5-HT2B antago therapy with a 5-HT2B (serotonin 2B receptor) antagonist nist is , preferably provided in a unitary dose of compound, are chosen from the group of diseases or disorders 10 between 25 and 50 mg of the active ingredient. consisting of mood disorders, anxiety disorders, eating dis 7: Combination Therapy with a 5-HT2C (Serotonin 2C orders, premenstrual syndrome, Somatoform disorders (ex Receptor) Antagonist Compound cluding pain disorders), factitious disorders, dissociative dis The mental disorders which can be treated using com orders, sexual and gender disorders, sleep disorders, pounds having a high selective affinity for the 5-HT2A and adjustment disorders, impulse control disorders, Substance 15 D4 receptor, for instance pipamperon, in a combination related disorder, personality disorders, antisocial behaviour, therapy with a 5-HT2C (serotonin 2C receptor) antagonist bereavement, occupational problem, problems related to compound, are chosen from the group of diseases or disorders abuse or neglect and pain disorders. consisting of mood disorders, anxiety disorders, eating dis The present invention thus relates to the use of pipamperon orders, premenstrual syndrome, Somatoform disorders (ex or a pharmaceutically acceptable salt thereof for the prepara cluding pain disorders), factitious disorders, dissociative dis tion of a medicament for treating the underlying emotion orders, sexual and gender disorders, sleep disorders, dysregulation of a non-cognitive mental disease or disorder adjustment disorders, impulse control disorders, Substance selected from the group of diseases and disorders consisting related disorder, personality disorders, antisocial behaviour, of mood disorders, anxiety disorders, eating disorders, pre bereavement, occupational problem, problems related to menstrual syndrome, Somatoform disorders (excluding pain 25 abuse or neglect and pain disorders. disorders), factitious disorders, dissociative disorders, sexual The present invention thus relates to the use of pipamperon and gender disorders, sleep disorders, adjustment disorders, or a pharmaceutically acceptable salt thereof for the prepara impulse control disorders, Substance-related disorder, per tion of a medicament for treating the underlying emotion Sonality disorders, antisocial behaviour, bereavement, occu dysregulation of a non-cognitive mental disease or disorder pational problem, problems related to abuse or neglect, char 30 selected from the group of diseases and disorders consisting acterized in that pipamperon or said pharmaceutically of mood disorders, anxiety disorders, eating disorders, pre acceptable salt thereof is administered simultaneously with, menstrual syndrome, somatoform disorders (excluding pain separate from or prior to the administration of a 5-HT2B disorders), factitious disorders, dissociative disorders, sexual antagonist compound to augment the therapeutic effect or to and gender disorders, sleep disorders, adjustment disorders, provide a faster onset of the therapeutic effect of said 5-HT2B 35 impulse control disorders, Substance-related disorder, per antagonist compound, further characterized in that pipam Sonality disorders, antisocial behaviour, bereavement, occu peron is to be administered to a patient in a daily dose ranging pational problem, problems related to abuse or neglect, char between 5 and 15 mg of the active ingredient. acterized in that pipamperon or said pharmaceutically The present invention thus relates to the use of pipamperon acceptable salt thereof is administered simultaneously with, or a pharmaceutically acceptable salt thereof for the prepara 40 separate from or prior to the administration of a 5-HT2C tion of a medicament for treating the underlying emotion antagonist compound to augment the therapeutic effect or to dysregulation of pain disorders, characterized in that pipam provide a faster onset of the therapeutic effect of said 5-HT2C peron or said pharmaceutically acceptable salt thereof is antagonist compound, further characterized in that pipam administered simultaneously with, separate from or prior to peron is to be administered to a patient in a daily dose ranging the administration of a 5-HT2B antagonist compound to aug 45 between 5 and 15 mg of the active ingredient. ment the therapeutic effect or to provide a faster onset of the The present invention thus relates to the use of pipamperon therapeutic effect of said 5-HT2B antagonist compound, fur or a pharmaceutically acceptable salt thereof for the prepara ther characterized in that pipamperon is to be administered to tion of a medicament for treating the underlying emotion a patient in a daily dose ranging between 5 and 15 mg of the dysregulation of pain disorders, characterized in that pipam active ingredient. 50 peron or said pharmaceutically acceptable salt thereof is According to a preferred embodiment, the invention relates administered simultaneously with, separate from or prior to to the uses as described above, wherein said 5-HT2B antago the administration of a 5-HT2C antagonist compound to aug nist compound is agomelatine or a pro-drug or an active ment the therapeutic effect or to provide a faster onset of the metabolite thereof, or a pharmaceutically acceptable salt therapeutic effect of said 5-HT2C antagonist compound, fur thereof. Preferably, agomelatine is to be administered in a 55 ther characterized in that pipamperon is to be administered to daily dose ranging between 25 and 50 mg of the active ingre a patient in a daily dose ranging between 5 and 15 mg of the dient. active ingredient. The invention also relates to a pharmaceutical composition According to a preferred embodiment, the invention relates comprising (a) pipamperon, and (b) a 5-HT2B antagonist, to the uses as described above, wherein said 5-HT2C antago preferably agomelatine or a pro-drug or an active metabolite 60 nist compound is chosen from the group consisting of SB thereof, or a pharmaceutically acceptable salt thereof, as a 243213 and agomelatine or a pro-drug oran active metabolite combined preparation for simultaneous, separate or sequen thereof, or a pharmaceutically acceptable salt thereof. Pref tial use for treating the underlying emotion dysregulation of a erably, agomelatine is to be administered in a daily dose mental disease or disorder which is chosen from the group of ranging between 25 and 50 mg of the active ingredient. diseases or disorders consisting of mood disorders, anxiety 65 The invention also relates to a pharmaceutical composition disorders, eating disorders, premenstrual syndrome, Somato comprising (a) pipamperon, and (b) a 5-HT2C antagonist, form disorders (excluding pain disorders), factitious disor preferably chosen from the group consisting of SB 243213 US 8,304,431 B2 23 24 and agomelatine or a pro-drug oran active metabolite thereof, Disease, dementia due to Huntington Disease, dementia due or a pharmaceutically acceptable salt thereof, as a combined to Pick Disease, dementia due to Creutzfeldt-Jacob Disease, preparation for simultaneous, separate or sequential use for amnestic disorders due to a general medical condition, Sub treating the underlying emotion dysregulation of a mental stance-induced persisting amnestic disorder, mild cognitive disease or disorder which is chosen from the group of diseases impairment disorder and other cognitive disorders. or disorders consisting of mood disorders, anxiety disorders, The present invention thus relates to the use of pipamperon eating disorders, premenstrual syndrome, Somatoform disor or a pharmaceutically acceptable salt thereof for the prepara ders (excluding pain disorders), factitious disorders, disso tion of a medicament for treating the underlying emotion ciative disorders, sexual and gender disorders, sleep disor dysregulation of a cognitive disorder selected from the group ders, adjustment disorders, impulse control disorders, 10 of diseases and disorders consisting of Alzheimer Disease, Substance-related disorder, personality disorders, antisocial Substance-induced persisting dementia, Vascular dementia, behaviour, bereavement, occupational problem, problems dementia due to HIV disease, dementia due to head trauma, related to abuse or neglect and pain disorders. dementia due to Parkinson Disease, dementia due to Hunting The present invention also relates to a pharmaceutical com ton Disease, dementia due to Pick Disease, dementia due to position as described above wherein pipamperon is provided 15 Creutzfeldt-Jacob Disease, amnestic disorders due to a gen in a unitary dose of between 5 and 15 mg of the active eral medical condition, Substance-induced persisting amnes ingredient and wherein said 5-HT2C antagonist is ago tic disorder, mild cognitive impairment disorder and other melatine, preferably provided in a unitary dose of between 25 cognitive disorders, characterized in that pipamperon or said and 50 mg of the active ingredient. pharmaceutically acceptable salt thereof is administered 8: Combination Therapy with a 5-HT3 (Serotonin 3 Recep simultaneously with, separate from or prior to the adminis tor) Antagonist Compound tration of a 5-HT6 antagonist compound to augment the The mental disorders which can be treated using com therapeutic effect or to provide a faster onset of the therapeu pounds laving a high selective affinity for the 5-HT2A and D4 tic effect of said 5-HT6 antagonist compound, further char receptor, for instance pipamperon, in a combination therapy acterized in that pipamperon is to be administered to a patient with a 5-HT3 (serotonin 3 receptor) antagonist compound, 25 in a daily dose ranging between 5 and 15 mg of the active are substance-related disorders. ingredient. The present invention thus relates to the use of pipamperon According to a preferred embodiment, the invention relates or a pharmaceutically acceptable salt thereof for the prepara to the use as described above, wherein said 5-HT6 antagonist tion of a medicament for treating the underlying emotion compound is chosen from the group consisting of dysregulation of substance-related disorders, characterized in 30 SB-271046, 742457 and 271046 or a pro-drug or an active that pipamperon or said pharmaceutically acceptable salt metabolite thereof, or a pharmaceutically acceptable salt thereof is administered simultaneously with, separate from or thereof. prior to the administration of a 5-HT3 antagonist compound The invention also relates to a pharmaceutical composition to augment the therapeutic effect or to provide a faster onset comprising (a)pipamperon, and (b) a 5-HT6 antagonist, pref of the therapeutic effect of said 5-HT3 antagonist compound, 35 erably chosen from the group consisting of SB-271046, further characterized in that pipamperon is to be administered 742457 and 271046 or a pro-drug or an active metabolite to a patientina daily dose ranging between 5 and 15 mg of the thereof, or a pharmaceutically acceptable salt thereof, as a active ingredient. combined preparation for simultaneous, separate or sequen According to a preferred embodiment, the invention relates tial use for treating the underlying emotion dysregulation of a to the use as described above, wherein said 5-HT3 antagonist 40 mental disease or disorder which is chosen from the group of compound is or a pro-drug or an active metabo diseases or disorders consisting of Alzheimer Disease, Sub lite thereof, or a pharmaceutically acceptable salt thereof. stance-induced persisting dementia, vascular dementia, Preferably, ondansetron is to be administered in a daily dose dementia due to HIV disease, dementia due to head trauma, ranging between 8 and 32 mg of the active ingredient. dementia due to Parkinson Disease, dementia due to Hunting The invention also relates to a pharmaceutical composition 45 ton Disease, dementia due to Pick Disease, dementia due to comprising (a) pipamperon, and (b) a 5-HT3 antagonist, pref Creutzfeldt-Jacob Disease, amnestic disorders due to a gen erably ondansetron or a pro-drug or an active metabolite eral medical condition, Substance-induced persisting amnes thereof, or a pharmaceutically acceptable salt thereof, as a tic disorder, mild cognitive impairment disorder and other combined preparation for simultaneous, separate or sequen cognitive disorders. tial use for treating the underlying emotion dysregulation of 50 10: Combination Therapy with an Acetylcholinesterase Substance-related disorders. Inhibitor Compound The invention also relates to a pharmaceutical composition The mental disorders which can be treated using com as described above wherein pipamperon is provided in a pounds having a high selective affinity for the 5-HT2A and unitary dose of between 5 and 15 mg of the active ingredient D4 receptor, for instance pipamperon, in a combination and wherein said 5-HT3 antagonist is ondansetron, prefer 55 therapy with an acetylcholinesterase inhibitor compound, are ably provided in a unitary dose of between 8 and 32 mg of the chosen from the group of diseases or disorders consisting of active ingredient. Alzheimer Disease, Substance-induced persisting dementia, 9: Combination Therapy with a 5-HT6 (Serotonin 6 Recep vascular dementia, dementia due to HIV disease, dementia tor) Antagonist Compound due to head trauma, dementia due to Parkinson Disease, The mental disorders which can be treated using com 60 dementia due to Huntington Disease, dementia due to Pick pounds having a high selective affinity for the 5-HT2A and Disease, dementia due to Creutzfeldt-Jacob Disease, amnes D4 receptor, for instance pipamperon, in a combination tic disorders due to a general medical condition, Substance therapy with a 5-HT6 (serotonin 6 receptor) antagonist com induced persisting amnestic disorder, mild cognitive impair pound, are chosen from the group of diseases or disorders ment disorder and other cognitive disorders. consisting of Alzheimer Disease, Substance-induced persist 65 The present invention thus relates to the use of pipamperon ing dementia, Vascular dementia, dementia due to HIV dis or a pharmaceutically acceptable salt thereof for the prepara ease, dementia due to head trauma, dementia due to Parkinson tion of a medicament for treating the underlying emotion US 8,304,431 B2 25 26 dysregulation of a cognitive disorder selected from the group in a unitary dose of between 5 and 15 mg of the active of diseases and disorders consisting of Alzheimer Disease, ingredient and wherein said acetylcholinesterase inhibitor is Substance-induced persisting dementia, Vascular dementia, galantamine (preferably extended release formulation), pref dementia due to HIV disease, dementia due to head trauma, erably provided in a unitary dose of between 8 and 24 mg of dementia due to Parkinson Disease, dementia due to Hunting the active ingredient. ton Disease, dementia due to Pick Disease, dementia due to 11: Combination Therapy with an Adenosine A2a Receptor Creutzfeldt-Jacob Disease, amnestic disorders due to a gen Antagonist Compound eral medical condition, Substance-induced persisting amnes The mental disorder which can be treated using com tic disorder, mild cognitive impairment disorder, other cog pounds having a high selective affinity for the 5-HT2A and nitive disorders, characterized in that pipamperon or said 10 D4 receptor, for instance pipamperon, in a combination pharmaceutically acceptable salt thereof is administered therapy with an adenosine A2a receptor antagonist com simultaneously with, separate from or prior to the adminis pound, is Parkinson disease. tration of an acetylcholinesterase inhibitor compound to aug The present invention thus relates to the use of pipamperon ment the therapeutic effect or to provide a faster onset of the or a pharmaceutically acceptable salt thereof for the prepara therapeutic effect of said acetylcholinesterase inhibitor com 15 tion of a medicament for treating the underlying emotion pound, further characterized in that pipamperon is to be dysregulation of Parkinson disease, characterized in that administered to a patient in a daily dose ranging between 5 pipamperon or said pharmaceutically acceptable salt thereof and 15 mg of the active ingredient. is administered simultaneously with, separate from or prior to According to a preferred embodiment, the invention relates the administration of an adenosine A2a receptor antagonist to the use as described above, wherein said acetylcholinest compound to augment the therapeutic effect or to provide a erase inhibitor compound is chosen from the group consisting faster onset of the therapeutic effect of said adenosine A2a oftacrine, rivastigmine tartrate, rivastigmine, physostigmine, receptor antagonist compound, further characterized in that phenserine tartrate, metrifonate, huperzine A, galantamine pipamperon is to be administered to a patient in a daily dose (preferably extended release formulation), donezepil, dichlo ranging between 5 and 15 mg of the active ingredient. rvos and anseculin hydrochloride, preferably tartrate, or a 25 According to a preferred embodiment, the invention relates pro-drug or an active metabolite thereof, or a pharmaceuti to the use as described above, wherein said adenosine A2a cally acceptable sat thereof. Preferably, rivastigmine tartrate receptor antagonist compound is KW-6002 or a pro-drug or is to be administered in a daily dose ranging between 3 and 12 an active metabolite thereof, or a pharmaceutically accept mg of the active ingredient. Preferably, phenserine tartrate is able salt thereof. Preferably, KW-6002 is to be administered to be administered in a daily dose ranging between 20 and 30 30 in a daily dose ranging between 40 and 80 mg of the active mg of the active ingredient. Preferably, galantamine (ex ingredient. tended release formulation) is to be administered in a daily The invention also relates to a pharmaceutical composition dose ranging between 8 and 24 mg of the active ingredient. comprising (a) pipamperon, and (b) an adenosine A2a recep The invention also relates to a pharmaceutical composition tor antagonist, preferably KW-6002 or a pro-drug oran active comprising (a) pipamperon, and (b) an acetylcholinesterase 35 metabolite thereof, or a pharmaceutically acceptable salt inhibitor, preferably chosen from the group consisting of thereof, as a combined preparation for simultaneous, separate tacrine, rivastigmine tartrate, rivastigmine, physostigmine, or sequential use for treating the underlying emotion dysregu phenserine tartrate, metrifonate, huperzine A, galantamine lation of Parkinson disease. (preferably extended release formulation), donezepil, dichlo The invention also relates to a pharmaceutical composition rvos and anseculin hydrochloride, preferably tartrate, or a 40 as described above wherein pipamperon is provided in a pro-drug or an active metabolite thereof, or a pharmaceuti unitary dose of between 5 and 15 mg of the active ingredient cally acceptable salt thereof, as a combined preparation for and wherein said acetylcholinesterase inhibitor is KW-6002, simultaneous, separate or sequential use for treating the preferably provided in a unitary dose of between 40 and 80 underlying emotion dysregulation of a mental disease or dis mg of the active ingredient. order which is chosen from the group of diseases or disorders 45 12: Combination Therapy with an Adrenergic Transmitter consisting of Alzheimer Disease, Substance-related persisting Releaser dementia, Vascular dementia, dementia due to HIV disease, The mental disorders which can be treated using com dementia due to head trauma, dementia due to Parkinson pounds having a high selective affinity for the 5-HT2A and Disease, dementia due to Huntington Disease, dementia due D4 receptor, for instance pipamperon, in a combination to Pick Disease, dementia due to Creutzfeldt-Jacob Disease, 50 therapy with an adrenergic transmitter releaser, are chosen amnestic disorders due to a general medical condition, Sub from the group of diseases or disorders consisting of mood stance-induced persisting amnestic disorder, mild cognitive disorders, anxiety disorders, eating disorders, premenstrual impairment disorder and other cognitive disorders. syndrome, Somatoform disorders (excluding pain disorders), The invention also relates to a pharmaceutical composition factitious disorders, dissociative disorders, sexual and gender as described above wherein pipamperon is provided in a 55 identity disorders, adjustment disorders, impulse control dis unitary dose of between 5 and 15 mg of the active ingredient orders, personality disorders, bereavement, occupational and wherein said acetylcholinesterase inhibitor is rivastig problem, problems related to abuse or neglect and pain dis mine tartrate, preferably provided in a unitary dose of orders. between 3 and 12 mg of the active ingredient. The present invention thus relates to the use of pipamperon The invention further relates to a pharmaceutical compo 60 or a pharmaceutically acceptable salt thereof for the prepara sition as described above wherein pipamperon is provided in tion of a medicament for treating the underlying emotion a unitary dose of between 5 and 15 mg of the active ingredient dysregulation of a non-cognitive mental disease or disorder and wherein said acetylcholinesterase inhibitor is phenserine selected from the group of diseases and disorders consisting tartrate, preferably provided in a unitary dose of between 20 of mood disorders, anxiety disorders, eating disorders, pre and 30 mg of the active ingredient. 65 menstrual syndrome, Somatoform disorders (excluding pain In addition, the invention relates to a pharmaceutical com disorders), factitious disorders, dissociative disorders, sexual position as described above wherein pipamperon is provided and gender identity disorders, adjustment disorders, impulse US 8,304,431 B2 27 28 control disorders, personality disorders, bereavement, occu dysregulation of a non-cognitive mental disease or disorder pational problem and problems related to abuse or neglect, selected from the group of diseases and disorders consisting characterized in that pipamperon or said pharmaceutically of mood disorders, anxiety disorders, eating disorders, pre acceptable salt thereof is administered simultaneously with, menstrual syndrome, Somatoform disorders (excluding pain separate from or prior to the administration of an adrenergic disorders), factitious disorders, dissociative disorders, sexual transmitter releaser compound to augment the therapeutic and gender identity disorders, sleep disorders, adjustment effect or to provide a faster onset of the therapeutic effect of disorders, impulse control disorders, personality disorders, said adrenergic transmitter releaser compound, further char bereavement, occupational problem and problems related to acterized in that pipamperon is to be administered to a patient abuse or neglect, characterized in that pipamperon or said in a daily dose ranging between 5 and 15 mg of the active 10 pharmaceutically acceptable salt thereof is administered ingredient. simultaneously with, separate from or prior to the adminis The present invention thus relates to the use of pipamperon tration of a alpha 1 adrenoreceptor antagonist compound to or a pharmaceutically acceptable salt thereof for the prepara augment the therapeutic effect or to provide a faster onset of tion of a medicament for treating the underlying emotion the therapeutic effect of said alpha 1 adrenoreceptor antago dysregulation of pain disorders, characterized in that pipam 15 nist compound, further characterized in that pipamperon is to peron or said pharmaceutically acceptable salt thereof is be administered to a patient in a daily dose ranging between 5 administered simultaneously with, separate from or prior to and 15 mg of the active ingredient. the administration of an adrenergic transmitter releaser com The present invention thus relates to the use of pipamperon pound to augment the therapeutic effect or to provide a faster or a pharmaceutically acceptable salt thereof for the prepara onset of the therapeutic effect of said adrenergic transmitter tion of a medicament for treating the underlying emotion releaser compound, further characterized in that pipamperon dysregulation of pain disorders, characterized in that pipam is to be administered to a patient in a daily dose ranging peron or said pharmaceutically acceptable salt thereof is between 5 and 15 mg of the active ingredient. administered simultaneously with, separate from or prior to According to a preferred embodiment, the invention relates the administration of an alpha 1 adrenoreceptor antagonist to the uses as described above, wherein said adrenergic trans 25 compound to augment the therapeutic effect or to provide a mitter releaser compound is pipoxazole or a pro-drug or an faster onset of the therapeutic effect of said alpha 1 adreno active metabolite thereof, or a pharmaceutically acceptable receptor antagonist compound, further characterized in that salt thereof. Preferably, pipoxazole is to be administered in a pipamperon is to be administered to a patient in a daily dose daily dose ranging between 30 and 60 mg of the active ingre ranging between 5 and 15 mg of the active ingredient. dient. 30 The present invention thus relates to the use of pipamperon The invention also relates to a pharmaceutical composition or a pharmaceutically acceptable salt thereof for the prepara comprising (a) pipamperon, and (b) an adrenergic transmitter tion of a medicament for treating the underlying emotion releaser, preferably pipoxazole, or a pro-drug or an active dysregulation of Parkinson disease, characterized in that metabolite thereof, or a pharmaceutically acceptable salt pipamperon or said pharmaceutically acceptable salt thereof thereof, as a combined preparation for simultaneous, separate 35 is administered simultaneously with, separate from or prior to or sequential use for treating the underlying emotion dysregu the administration of an alpha 1 adrenoreceptor antagonist lation of amental disease or disorder which is chosen from the compound to augment the therapeutic effect or to provide a group of diseases or disorders consisting of mood disorders, faster onset of the therapeutic effect of said alpha 1 adreno anxiety disorders, eating disorders, premenstrual syndrome, receptor antagonist compound, further characterized in that Somatoform disorders (excluding pain disorders), factitious 40 pipamperon is to be administered to a patient in a daily dose disorders, dissociative disorders, sexual and gender identity ranging between 5 and 15 mg of the active ingredient. disorders, adjustment disorders, impulse control disorders, According to a preferred embodiment, the invention relates personality disorders, bereavement, occupational problem, to the uses as described above, wherein said alpha 1 adreno problems related to abuse or neglect and pain disorders. receptor antagonist compound is chosen from the group con The invention also relates to a pharmaceutical composition 45 sisting of SDZ NVI 085 and flesinoxan or a pro-drug or an as described above wherein pipamperon is provided in a active metabolite thereof, or a pharmaceutically acceptable unitary dose of between 5 and 15 mg of the active ingredient salt thereof. and wherein said adrenergic transmitter releaser is The invention also relates to a pharmaceutical composition pipoxazole, preferably provided in a unitary dose of between comprising (a) pipamperon, and (b) an alpha 1 adrenorecep 30 and 60 mg of the active ingredient. 50 torantagonist, preferably chosen from the group consisting of 13: Combination Therapy with an Alpha 1 Adrenoreceptor SDZ NVI 085 and flesinoxan or a pro-drug or an active Antagonist metabolite thereof, or a pharmaceutically acceptable salt The mental disorders which can be treated using com thereof, as a combined preparation for simultaneous, separate pounds having a high selective affinity for the 5-HT2A and or sequential use for treating the underlying emotion dysregu D4 receptor, for instance pipamperon, in a combination 55 lation of amental disease or disorder which is chosen from the therapy with an alpha 1 adrenoreceptor antagonist, are chosen group of diseases or disorders consisting of mood disorders, from the group of diseases or disorders consisting of mood anxiety disorders, eating disorders, premenstrual syndrome, disorders, anxiety disorders, eating disorders, premenstrual Somatoform disorders (excluding pain disorders), factitious syndrome, Somatoform disorders (excluding pain disorders), disorders, dissociative disorders, sexual and gender identity factitious disorders, dissociative disorders, sexual and gender 60 disorders, sleep disorders, adjustment disorders, impulse identity disorders, sleep disorders, adjustment disorders, control disorders, personality disorders, bereavement, occu impulse control disorders, personality disorders, bereave pational problem, problems related to abuse or neglect, pain ment, occupational problem, problems related to abuse or disorders and Parkinson disease. neglect, pain disorders and Parkinson disease. 14: Combination Therapy with an Alpha 2 Adrenoreceptor The present invention thus relates to the use of pipamperon 65 Antagonist or a pharmaceutically acceptable salt thereof for the prepara The mental disorders which can be treated using com tion of a medicament for treating the underlying emotion pounds having a high selective affinity for the 5-HT2A and US 8,304,431 B2 29 30 D4 receptor, for instance pipamperon, in a combination ders, sleep disorders, adjustment disorders, impulse control therapy with an alpha2-adrenoreceptor antagonist, are chosen disorders, Substance related disorders, personality disorders, from the group of diseases or disorders consisting of mood bereavement, occupational problem, problems related to disorders, anxiety disorders, psychotic disorders, eating dis abuse or neglect and pain disorders. orders, premenstrual syndrome, Somatoform disorders (ex The invention also relates to a pharmaceutical composition cluding pain disorders), factitious disorders, dissociative dis as described above wherein pipamperon is provided in a orders, sexual and gender identity disorders, sleep disorders, unitary dose of between 5 and 15 mg of the active ingredient adjustment disorders, impulse control disorders, Substance and wherein said alpha 2 adrenoreceptor antagonist is Ida related disorders, personality disorders, bereavement, occu Zoxan, preferably provided in a unitary dose of between 5 and pational problem, problems related to abuse or neglect and 10 40 mg of the active ingredient. pain disorders. 15: Combination Therapy with an AMPA Receptor Mediator The present invention thus relates to the use of pipamperon Compound or a pharmaceutically acceptable salt thereof for the prepara The mental disorders which can be treated using com tion of a medicament for treating the underlying emotion pounds having a high selective affinity for the 5-HT2A and dysregulation of a non-cognitive mental disease or disorder 15 D4 receptor, for instance pipamperon, in a combination selected from the group of diseases and disorders consisting therapy with an AMPA (alpha-amino-3-hydroxy-5-methyl-4- of mood disorders, anxiety disorders, psychotic disorders, isoxazole propionate) receptor mediator compound, are cho eating disorders, premenstrual syndrome, Somatoform disor Sen from the group of diseases or disorders consisting of ders (excluding pain disorders), factitious disorders, disso mood disorders, anxiety disorders, psychotic disorders, eat ciative disorders, sexual and gender identity disorders, sleep ing disorders, premenstrual syndrome, somatoform disorders disorders, adjustment disorders, impulse control disorders, (excluding pain disorders), factitious disorders, dissociative Substance related disorders, personality disorders, bereave disorders, sleep disorders, adjustment disorders, impulse ment, occupational problem and problems related to abuse or control disorders, pervasive development disorders, disrup neglect, characterized in that pipamperon or said pharmaceu tive behaviour disorders, Substance-induced disorders, per tically acceptable salt thereof is administered simultaneously 25 Sonality disorders, psychological factors affecting medical with, separate from or prior to the administration of a alpha 2 conditions, malingering, antisocial behaviour, bereavement, adrenoreceptor antagonist compound to augment the thera occupational problem, identity problem, problems related to peutic effect or to provide a faster onset of the therapeutic abuse or neglect, pain disorders, delirium, Alzheimer Dis effect of said alpha 2 adrenoreceptor antagonist compound, ease, Substance-related persisting dementia, Vascular demen further characterized in that pipamperon is to be administered 30 tia, dementia due to HIV disease, dementia due to head to a patientina daily dose ranging between 5 and 15 mg of the trauma, dementia due to Parkinson Disease, dementia due to active ingredient. Huntington Disease, dementia due to Pick Disease, dementia The present invention thus relates to the use of pipamperon due to Creutzfeldt-Jacob Disease, amnestic disorders due to a or a pharmaceutically acceptable salt thereof for the prepara general medical condition, Substance-induced persisting tion of a medicament for treating the underlying emotion 35 amnestic disorder, mild cognitive impairment disorder and dysregulation of pain disorders, characterized in that pipam other cognitive disorders. peron or said pharmaceutically acceptable salt thereof is The present invention thus relates to the use of pipamperon administered simultaneously with, separate from or prior to or a pharmaceutically acceptable salt thereof for the prepara the administration of an alpha 2 adrenoreceptor antagonist tion of a medicament for treating the underlying emotion compound to augment the therapeutic effect or to provide a 40 dysregulation of a non-cognitive mental disease or disorder faster onset of the therapeutic effect of said alpha 2 adreno selected from the group of diseases and disorders consisting receptor antagonist compound, further characterized in that of mood disorders, anxiety disorders, psychotic disorders, pipamperon is to be administered to a patient in a daily dose eating disorders, premenstrual syndrome, Somatoform disor ranging between 5 and 15 mg of the active ingredient. ders (excluding pain disorders), factitious disorders, disso According to a preferred embodiment, the invention relates 45 ciative disorders, sleep disorders, adjustment disorders, to the uses as described above, wherein said alpha 2 adreno impulse control disorders, pervasive development disorders, receptor antagonist compound is chosen from the group con disruptive behaviour disorders, substance-related disorders, sisting of UK-14304, Sunepitron, mirtazepine, idazoxan, personality disorders, psychological factors affecting medi fluparoxan, A75200 and (R)-A 75200, preferably sunepitron cal conditions, malingering, antisocial behaviour, bereave oridazoxan, or a pro-drug or an active metabolite thereof, or 50 ment, occupational problem, identity problem and problems a pharmaceutically acceptable salt thereof. Preferably, ida related to abuse or neglect, characterized in that pipamperon Zoxan is to be administered in a daily dose ranging between 5 or said pharmaceutically acceptable salt thereof is adminis and 40 mg of the active ingredient. tered simultaneously with, separate from or prior to the The invention also relates to a pharmaceutical composition administration of an AMPA receptor mediator compound to comprising (a) pipamperon, and (b) an alpha 2 adrenorecep 55 augment the therapeutic effect or to provide a faster onset of torantagonist, preferably chosen from the group consisting of the therapeutic effect of said AMPA receptor mediator com UK-14304, Sunepitron, mirtazepine, idazoxan, fluparoxan, pound, further characterized in that pipamperon is to be A75200 and (R)-A75200, preferably sunepitron oridazoxan, administered to a patient in a daily dose ranging between 5 or a pro-drug or an active metabolite thereof, or a pharma and 15 mg of the active ingredient. ceutically acceptable salt thereof, as a combined preparation 60 The present invention thus relates to the use of pipamperon for simultaneous, separate or sequential use for treating the or a pharmaceutically acceptable salt thereof for the prepara underlying emotion dysregulation of a mental disease or dis tion of a medicament for treating the underlying emotion order which is chosen from the group of diseases or disorders dysregulation of pain disorders, characterized in that pipam consisting of mood disorders, anxiety disorders, psychotic peron or said pharmaceutically acceptable salt thereof is disorders, eating disorders, premenstrual syndrome, Somato 65 administered simultaneously with, separate from or prior to form disorders (excluding pain disorders), factitious disor the administration of an AMPA receptor mediator compound ders, dissociative disorders, sexual and gender identity disor to augment the therapeutic effect or to provide a faster onset US 8,304,431 B2 31 32 of the therapeutic effect of said AMPA receptor mediator D4 receptor, for instance pipamperon, in a combination compound, further characterized in that pipamperon is to be therapy with an amphetamine compound, are attention-defi administered to a patient in a daily dose ranging between 5 cit disorders. and 15 mg of the active ingredient. The present invention thus relates to the use of pipamperon The present invention thus relates to the use of pipamperon or a pharmaceutically acceptable salt thereof for the prepara or a pharmaceutically acceptable salt thereof for the prepara tion of a medicament for treating the underlying emotion tion of a medicament for treating the underlying emotion dysregulation of attention deficit disorders, characterized in dysregulation of a cognitive mental disease or disorder that pipamperon or said pharmaceutically acceptable salt selected from the group of diseases and disorders consisting thereof is administered simultaneously with, separate from or 10 prior to the administration of an amphetamine compound to of delirium, Alzheimer Disease, Substance-induced persist augment the therapeutic effect or to provide a faster onset of ing dementia, Vascular dementia, dementia due to HIV dis the therapeutic effect of said amphetamine compound, further ease, dementia due to head trauma, dementia due to Parkinson characterized in that pipamperon is to be administered to a Disease, dementia due to Huntington Disease, dementia due patient in a daily dose ranging between 5 and 15 mg of the to Pick Disease, dementia due to Creutzfeldt-Jacob Disease, 15 active ingredient. amnestic disorders due to a general medical condition, Sub According to a preferred embodiment, the invention relates stance-induced persisting amnestic disorder, mild cognitive to the use as described above, wherein said amphetamine impairment disorder and other cognitive disorders, character compound is methylphenidate (preferably administered by a ized in that pipamperon or said pharmaceutically acceptable transdermal system) or a pro-drug or an active metabolite salt thereof is administered simultaneously with, separate thereof, or a pharmaceutically acceptable salt thereof. from or prior to the administration of an AMPA receptor The invention also relates to a pharmaceutical composition mediator compound to augment the therapeutic effect or to comprising (a) pipamperon, and (b) an amphetamine, prefer provide a faster onset of the therapeutic effect of said AMPA ably methylphenidate (preferably administered by a transder receptor mediator compound, further characterized in that mal system) or a pro-drug or an active metabolite thereof, or pipamperon is to be administered to a patient in a daily dose 25 a pharmaceutically acceptable salt thereof, as a combined ranging between 5 and 15 mg of the active ingredient. preparation for simultaneous, separate or sequential use for According to a preferred embodiment, the invention relates treating the underlying emotion dysregulation of attention to the uses as described above, wherein said AMPA receptor deficit disorders. mediator compound is chosen from the group consisting of 17: Combination Therapy with an Amyloid Aggregation-In ampakine ORG 24448/CX-619, ampakine CX-717, ampak 30 hibitor Compound The mental disorders which can be treated using compounds ine CX-691 and ampakine CX-516, preferably ampakine having a high selective affinity for the 5-HT2A and D4 recep ORG 24448/CX-619, ampakine CX-717 or ampakine tor, for instance pipamperon, in a combination therapy with CX-691, or a pro-drug or an active metabolite thereof, or a an amyloid aggregation-inhibitor compound, are chosen pharmaceutically acceptable salt thereof. 35 from the group of diseases or disorders consisting of Alzhe The invention also relates to a pharmaceutical composition imer Disease, Substance-related persisting dementia, Vascular comprising (a) pipamperon, and (b) an AMPA receptor dementia, dementia due to HIV disease, dementia due to head mediator, preferably chosen from the group consisting of trauma, dementia due to Parkinson Disease, dementia due to ampakine ORG 24448/CX-619, ampakine CX-717, ampak Huntington Disease, dementia due to Pick Disease, dementia ine CX-691 and ampakine. CX-516, preferably ampakine 40 due to Creutzfeldt-Jacob Disease, amnestic disorders due to a ORG 24448/CX-619, ampakine CX-717 or ampakine general medical condition, Substance-induced persisting CX-691, or a pro-drug or an active metabolite thereof, or a amnestic disorder, mild cognitive impairment disorder and pharmaceutically acceptable salt thereof, as a combined other cognitive disorders. preparation for simultaneous, separate or sequential use for The present invention thus relates to the use of pipamperon treating the underlying emotion dysregulation of a mental 45 or a pharmaceutically acceptable salt thereof for the prepara disease or disorder which is chosen from the group of diseases tion of a medicament for treating the underlying emotion or disorders consisting of mood disorders, anxiety disorders, dysregulation of a cognitive mental disease or disorder psychotic disorders, eating disorders, premenstrual Syn selected from the group of diseases and disorders consisting drome. Somatoform disorders (excluding pain disorders), fac of Alzheimer Disease, Substance-related persisting dementia, titious disorders, dissociative disorders, sleep disorders, 50 vascular dementia, dementia due to HIV disease, dementia adjustment disorders, impulse control disorders, pervasive due to head trauma, dementia due to Parkinson Disease, development disorders, disruptive behaviour disorders, sub dementia due to Huntington Disease, dementia due to Pick stance-related disorders, personality disorders, psychological Disease, dementia due to Creutzfeldt-Jacob Disease, amnes factors affecting medical conditions, malingering, antisocial tic disorders due to a general medical condition, Substance behaviour, bereavement, occupational problem, identity 55 induced persisting amnestic disorder, mild cognitive impair problem, problems related to abuse or neglect, pain disorders, ment disorder and other cognitive disorders, characterized in delirium, Alzheimer Disease, Substance-induced persisting that pipamperon or said pharmaceutically acceptable salt dementia, Vascular dementia, dementia due to HIV disease, thereof is administered simultaneously with, separate from or dementia due to head trauma, dementia due to Parkinson prior to the administration of an amyloid aggregation-inhibi Disease, dementia due to Huntington Disease, dementia due 60 tor compound to augment the therapeutic effect or to provide to Pick Disease, dementia due to Creutzfeldt-Jacob Disease, a faster onset of the therapeutic effect of said amyloid aggre amnestic disorders due to a general medical condition, Sub gation-inhibitor compound, further characterized in that stance-induced persisting amnestic disorder, mild cognitive pipamperon is to be administered to a patient in a daily dose impairment disorder and other cognitive disorders. ranging between 5 and 15 mg of the active ingredient. 16: Combination Therapy with an Amphetamine Compound 65 According to a preferred embodiment, the invention relates The mental disorders which can be treated using com to the use as described above, wherein said amyloid aggrega pounds having a high selective affinity for the 5-HT2A and tion-inhibitor compound is chosen from the group consisting US 8,304,431 B2 33 34 of APAN and Alzhemed, or a pro-drug oran active metabolite syndrome, Somatoform disorders (excluding pain disorders), thereof, or a pharmaceutically acceptable salt thereof. Pref. factitious disorders, dissociative disorders, sexual and gender erably, Alzhemed is to be administered in a daily dose of identity disorders, sleep disorders, adjustment disorders, between 200 and 300 mg of the active ingredient. impulse control disorders, Substance related disorders, per The invention also relates to a pharmaceutical composition 5 Sonality disorders, bereavement, occupational problem, comprising (a) pipamperon, and (b) an amyloid aggregation problems related to abuse or neglect and pain disorders. inhibitor, preferably chosen from the group consisting of The present invention thus relates to the use of pipamperon APAN and Alzhemed, or a pro-drug or an active metabolite or a pharmaceutically acceptable salt thereof for the prepara thereof, or a pharmaceutically acceptable salt thereof, as a tion of a medicament for treating the underlying emotion combined preparation for simultaneous, separate or sequen 10 dysregulation of a non-cognitive mental disease or disorder tial use for treating the underlying emotion dysregulation of a selected from the group of diseases and disorders consisting mental disease or disorder which is chosen from the group of of mood disorders, anxiety disorders, eating disorders, pre diseases or disorders consisting of Alzheimer Disease, Sub menstrual syndrome, Somatoform disorders (excluding pain stance-related persisting dementia, Vascular dementia, disorders), factitious disorders, dissociative disorders, sexual dementia due to HIV disease, dementia due to head trauma, 15 and gender identity disorders, sleep disorders, adjustment dementia due to Parkinson Disease, dementia due to Hunting disorders, impulse control disorders, Substance related disor ton Disease, dementia due to Pick Disease, dementia due to ders, personality disorders, bereavement, occupational prob Creutzfeldt-Jacob Disease, amnestic disorders due to a gen lemand problems related to abuse or neglect, characterized in eral medical condition, Substance-induced persisting amnes that pipamperon or said pharmaceutically acceptable salt tic disorder, mild cognitive impairment disorder and other thereof is administered simultaneously with, separate from or cognitive disorders. prior to the administration of a beta 3 adrenoreceptoragonist The invention also relates to a pharmaceutical composition compound to augment the therapeutic effect or to provide a as described above wherein pipamperon is provided in a faster onset of the therapeutic effect of said beta 3 adrenore unitary dose of between 5 and 15 mg of the active ingredient ceptor agonist compound, further characterized in that and wherein said amyloid aggregation-inhibitoris Alzhemed, 25 pipamperon is to be administered to a patient in a daily dose preferably provided in a unitary dose of between 200 and 300 ranging between 5 and 15 mg of the active ingredient. mg of the active ingredient. The present invention thus relates to the use of pipamperon 18: Combination Therapy with an Androgen Receptor Modu or a pharmaceutically acceptable salt thereof for the prepara lator Compound tion of a medicament for treating the underlying emotion The mental disorders which can be treated using com 30 dysregulation of pain disorders, characterized in that pipam pounds having a high selective affinity for the 5-HT2A and peron or said pharmaceutically acceptable salt thereof is D4 receptor, for instance pipamperon, in a combination administered simultaneously with, separate from or prior to therapy with an androgen receptor modulator compound, are the administration of an beta 3 adrenoreceptor agonist com sexual and gender identity disorders. pound to augment the therapeutic effect or to provide a faster The present invention thus relates to the use of pipamperon 35 onset of the therapeutic effect of said beta 3 adrenoreceptor or a pharmaceutically acceptable salt thereof for the prepara agonist compound, further characterized in that pipamperon tion of a medicament for treating the underlying emotion is to be administered to a patient in a daily dose ranging dysregulation of sexual and gender identity disorders, char between 5 and 15 mg of the active ingredient. acterized in that pipamperon or said pharmaceutically accept According to a preferred embodiment, the invention relates able salt thereof is administered simultaneously with, sepa 40 to the uses as described above, wherein said beta 3 adrenore rate from or prior to the administration of an androgen ceptor agonist compound is SR 586'1 or a pro-drug or an receptor modulator compound to augment the therapeutic active metabolite thereof, or a pharmaceutically acceptable effect or to provide a faster onset of the therapeutic effect of salt thereof. said androgen receptor modulator compound, further charac The invention also relates to a pharmaceutical composition terized in that pipamperon is to be administered to a patient in 45 comprising (a) pipamperon, and (b) a beta 3 adrenoreceptor a daily dose ranging between 5 and 15 mg of the active agonist, preferably SR 586.11 or a pro-drug or an active ingredient. metabolite thereof, or a pharmaceutically acceptable salt According to a preferred embodiment, the invention relates thereof, as a combined preparation for simultaneous, separate to the use as described above, wherein said androgen receptor or sequential use for treating the underlying emotion dysregu modulator compound is LGD2226 or a pro-drug or an active 50 lation of amental disease or disorder which is chosen from the metabolite thereof, or a pharmaceutically acceptable salt group of diseases or disorders consisting of mood disorders, thereof. anxiety disorders, eating disorders, premenstrual syndrome, The invention also relates to a pharmaceutical composition Somatoform disorders (excluding pain disorders), factitious comprising (a) pipamperon, and (b) an androgen receptor disorders, dissociative disorders, sexual and gender identity modulator, preferably LGD2226 or a pro-drug or an active 55 disorders, sleep disorders, adjustment disorders, impulse metabolite thereof, or a pharmaceutically acceptable salt control disorders, Substance related disorders, personality thereof, as a combined preparation for simultaneous, separate disorders, bereavement, occupational problem, problems or sequential use for treating the underlying emotion dysregu related to abuse or neglect and pain disorders. lation of sexual and gender identity disorders. 20: Combination Therapy with a Calcium Channel Modula 19: Combination Therapy with an Beta 3 Adrenoreceptor 60 tor Compound Agonist The mental disorders which can be treated using com The mental disorders which can be treated using com pounds having a high selective affinity for the 5-HT2A and pounds having a high selective affinity for the 5-HT2A and D4 receptor, for instance pipamperon, a combination therapy D4 receptor, for instance pipamperon, in a combination with a calcium channel modulator compound, are chosen therapy with an beta 3 adrenoreceptor agonist, are chosen 65 from the group of diseases or disorders consisting of Alzhe from the group of diseases or disorders consisting of mood imer Disease, Substance-related persisting dementia, Vascular disorders, anxiety disorders, eating disorders, premenstrual dementia, dementia due to HIV disease, dementia due to head US 8,304,431 B2 35 36 trauma, dementia due to Parkinson Disease, dementia due to therapy with a cannabioid receptor 1 (CB1) antagonist, are Huntington Disease, dementia due to Pick Disease, dementia chosen from the group of diseases or disorders consisting of due to Creutzfeldt-Jacob Disease, amnestic disorders due to a mood disorders, anxiety disorders, psychotic disorders, general medical condition, Substance-induced persisting Somatoform disorders (excluding pain disorders), factitious amnestic disorder, mild cognitive impairment disorder, other 5 disorders, dissociative disorders, sleep disorders, adjustment cognitive disorders and Parkinson disease. disorders, impulse control disorders, pervasive development The present invention thus relates to the use of pipamperon disorders, disruptive behaviour disorders, substance-related or a pharmaceutically acceptable salt thereof for the prepara disorders, personality disorders, psychological factors affect tion of a medicament for treating the underlying emotion ing medical conditions, malingering, antisocial behaviour, dysregulation of a cognitive mental disease or disorder 10 bereavement, occupational problem, identity problem, prob selected from the group of diseases and disorders consisting lems related to abuse or neglect, pain disorders and delirium. of Alzheimer Disease, Substance-related persisting dementia, The present invention thus relates to the use of pipamperon vascular dementia, dementia due to HIV disease, dementia or a pharmaceutically acceptable salt thereof for the prepara due to head trauma, dementia due to Parkinson Disease, tion of a medicament for treating the underlying emotion dementia due to Huntington Disease, dementia due to Pick 15 dysregulation of a non-cognitive mental disease or disorder Disease, dementia due to Creutzfeldt-Jacob Disease, amnes selected from the group of diseases and disorders consisting tic disorders due to a general medical condition, Substance mood disorders, anxiety disorders, psychotic disorders, induced persisting amnestic disorder, mild cognitive impair Somatoform disorders (excluding pain disorders), factitious ment disorder and other cognitive disorders, characterized in disorders, dissociative disorders, sleep disorders, adjustment that pipamperon or said pharmaceutically acceptable salt 20 disorders, impulse control disorders, pervasive development thereof is administered simultaneously with, separate from or disorders, disruptive behaviour disorders, substance-related prior to the administration of a calcium channel modulator disorders, personality disorders, psychological factors affect compound to augment the therapeutic effect or to provide a ing medical conditions, malingering, antisocial behaviour, faster onset of the therapeutic effect of said calcium channel bereavement, occupational problem, identity problem and modulator compound, further characterized in that pipam- 25 problems related to abuse or neglect, characterized in that peron is to be administered to a patient in a daily dose ranging pipamperon or said pharmaceutically acceptable salt thereof between 5 and 15 mg of the active ingredient. is administered simultaneously with, separate from or prior to The present invention thus relates to the use of pipamperon the administration of a cannabioid receptor 1 antagonist com or a pharmaceutically acceptable salt thereof for the prepara pound to augment the therapeutic effect or to provide a faster tion of a medicament for treating the underlying emotion 30 onset of the therapeutic effect of said cannabioid receptor dysregulation of Parkinson disease, characterized in that antagonist compound, further characterized in that pipam pipamperon or said pharmaceutically acceptable salt thereof peron is to be administered to a patient in a daily dose ranging is administered simultaneously with, separate from or prior to between 5 and 15 mg of the active ingredient. the administration of a calcium channel modulator compound The present invention thus relates to the use of pipamperon to augment the therapeutic effect or to provide a faster onset 35 or a pharmaceutically acceptable salt thereof for the prepara of the therapeutic effect of said calcium channel modulator tion of a medicament for treating the underlying emotion compound, further characterized in that pipamperon is to be dysregulation of pain disorders, characterized in that pipam administered to a patient in a daily dose ranging between 5 peron or said pharmaceutically acceptable salt thereof is and 15 mg of the active ingredient. administered simultaneously with, separate from or prior to According to a preferred embodiment, the invention relates 40 the administration of a cannabioid receptor 1 antagonist com to the uses as described above, wherein said calcium channel pound to augment the therapeutic effect or to provide a faster modulator compound is chosen from the group consisting of onset of the therapeutic effect of said cannabioid receptor 1 safinamide and MEM 1003, or a pro-drug or an active antagonist compound, further characterized in that pipam metabolite thereof, or a pharmaceutically acceptable salt peron is to be administered to a patient in a daily dose ranging thereof. 45 between 5 and 15 mg of the active ingredient. The invention also relates to a pharmaceutical composition The present invention thus relates to the use of pipamperon comprising (a) pipamperon, and (b) a calcium channel modu or a pharmaceutically acceptable salt thereof for the prepara lator, preferably chosen from the group consisting of Safina tion of a medicament for treating the underlying emotion mide and MEM 1003, or a pro-drug or an active metabolite dysregulation of delirium, characterized in that pipamperon thereof, or a pharmaceutically acceptable salt thereof, as a 50 or said pharmaceutically acceptable salt thereof is adminis combined preparation for simultaneous, separate or sequen tered simultaneously with, separate from or prior to the tial use for treating the underlying emotion dysregulation of a administration of a cannabioid receptor 1 antagonist com mental disease or disorder which is chosen from the group of pound to augment the therapeutic effect or to provide a faster diseases or disorders consisting of Alzheimer Disease, Sub onset of the therapeutic effect of said cannabioid receptor 1 stance-related persisting dementia, Vascular dementia, 55 antagonist compound, further characterized in that pipam dementia due to HIV disease, dementia due to head trauma, peron is to be administered to a patient in a daily dose ranging dementia due to Parkinson Disease, dementia due to Hunting between 5 and 15 mg of the active ingredient. ton Disease, dementia due to Pick Disease, dementia due to According to a preferred embodiment, the invention relates Creutzfeldt-Jacob Disease, amnestic disorders due to a gen to the uses as described above, wherein said cannabioid eral medical condition, Substance-induced persisting amnes- 60 receptor antagonist compound is SR141716 or a pro-drug or tic disorder, mild cognitive impairment disorder, other cog an active metabolite thereof, or a pharmaceutically accept nitive disorders and Parkinson disease. able salt thereof. 21: Combination Therapy with a Cannabioid Receptor 1 The invention also relates to a pharmaceutical composition (CB1) Antagonist comprising (a) pipamperon, and (b) a cannabioid receptor The mental disorders which can be treated using com- 65 antagonist, preferably SR 141716 or a pro-drug or an active pounds having a high selective affinity for the 5-HT2A and metabolite thereof, or a pharmaceutically acceptable salt D4 receptor, for instance pipamperon, in a combination thereof, as a combined preparation for simultaneous, separate US 8,304,431 B2 37 38 or sequential use for treating the underlying emotion dysregu Disease, dementia due to Creutzfeldt-Jacob Disease, amnes lation of amental disease or disorder which is chosen from the tic disorders due to a general medical condition, Substance group of diseases or disorders consisting of mood disorders, induced persisting amnestic disorder, mild cognitive impair anxiety disorders, psychotic disorders. Somatoform disorders ment disorder and other cognitive disorders, characterized in (excluding pain disorders), factitious disorders, dissociative that pipamperon or said pharmaceutically acceptable salt disorders, sleep disorders, adjustment disorders, impulse thereof is administered simultaneously with, separate from or control disorders, pervasive development disorders, disrup prior to the administration of a choline uptake enhancer com tive behaviour disorders, substance-related disorders, person pound to augment the therapeutic effect or to provide a faster ality disorders, psychological factors affecting medical con onset of the therapeutic effect of said cholineuptake enhancer ditions, malingering, antisocial behaviour, bereavement, 10 compound, further characterized in that pipamperon is to be occupational problem, identity problem, problems related to administered to a patient in a daily dose ranging between 5 abuse or neglect, pain disorders and delirium. and 15 mg of the active ingredient. 22: Combination Therapy with a Cathepsin K Inhibitor Com According to a preferred embodiment, the invention relates pound to the use as described above, wherein said choline uptake The mental disorders which can be treated using com 15 enhancer compound is MKC-231 or a pro-drug or an active pounds having a high selective affinity for the 5-HT2A and metabolite thereof, or a pharmaceutically acceptable salt D4 receptor, for instance pipamperon, in a combination thereof. Preferably, MKC-231 is to be administered in a daily therapy with a cathepsin K inhibitor compound, are pain dose of between 20 and 160 mg of the active ingredient. disorders. The invention also relates to a pharmaceutical composition The present invention thus relates to the use of pipamperon comprising (a) pipamperon, and (b) a choline uptake or a pharmaceutically acceptable salt thereof for the prepara enhancer, preferably MKC-231 or a pro-drug or an active tion of a medicament for treating the underlying emotion metabolite thereof, or a pharmaceutically acceptable salt dysregulation of pain disorders, characterized in that pipam thereof, as a combined preparation for simultaneous, separate peron or said pharmaceutically acceptable salt thereof is or sequential use for treating the underlying emotion dysregu administered simultaneously with, separate from or prior to 25 lation of amental disease or disorder which is chosen from the the administration of a cathepsin K inhibitor compound to group of diseases or disorders consisting of Alzheimer Dis augment the therapeutic effect or to provide a faster onset of ease, Substance-induced persisting dementia, Vascular the therapeutic effect of said cathepsin Kinhibitor compound, dementia, dementia due to HIV disease, dementia due to head further characterized in that pipamperon is to be administered trauma, dementia due to Parkinson Disease, dementia due to to a patientina daily dose ranging between 5 and 15 mg of the 30 Huntington Disease, dementia due to Pick Disease, dementia active ingredient. due to Creutzfeldt-Jacob Disease, amnestic disorders due to a According to a preferred embodiment, the invention relates general medical condition, substance-induced persisting to the use as described above, wherein said cathepsin K amnestic disorder, mild cognitive impairment disorder and inhibitor compound is 462795 or a pro-drug or an active other cognitive disorders. metabolite thereof, or a pharmaceutically acceptable salt 35 The invention also relates to a pharmaceutical composition thereof. as described above wherein pipamperon is provided in a The invention also relates to a pharmaceutical composition unitary dose of between 5 and 15 mg of the active ingredient comprising (a) pipamperon, and (b) a cathepsin K inhibitor, and wherein said choline uptake enhancer is MKC-231, pref preferably 462795 or a pro-drug or an active metabolite erably provided in a unitary dose of between 20 and 160 mg thereof, or a pharmaceutically acceptable salt thereof, as a 40 of the active ingredient. combined preparation for simultaneous, separate or sequen 24: Combination Therapy with a COX-2 Inhibitor Compound tial use for treating the underlying emotion dysregulation of The mental disorders which can be treated using com pain disorders. pounds having a high selective affinity for the 5-HT2A and 23: Combination Therapy with a Choline Uptake Enhancer D4 receptor, for instance pipamperon, in a combination Compound 45 therapy with a COX-2 inhibitor compound, are pain disor The mental disorders which can be treated using com ders. pounds having a high selective affinity for the 5-HT2A and The present invention thus relates to the use of pipamperon D4 receptor, for instance pipamperon, in a combination or a pharmaceutically acceptable salt thereof for the prepara therapy with a choline uptake enhancer compound, are cho tion of a medicament for treating the underlying emotion Sen from the group of diseases o' disorders consisting of 50 dysregulation of pain disorders, characterized in that pipam Alzheimer Disease, Substance-induced persisting dementia, peron or said pharmaceutically acceptable salt thereof is vascular dementia, dementia due to HIV disease, dementia administered simultaneously with, separate from or prior to due to head trauma, dementia due to Parkinson Disease, the administration of a COX-2 inhibitor compound to aug dementia due to Huntington Disease, dementia due to Pick ment the therapeutic effect or to provide a faster onset of the Disease, dementia due to Creutzfeldt-Jacob Disease, amnes 55 therapeutic effect of said COX-2 inhibitor compound, further tic disorders due to a general medical condition, Substance characterized in that pipamperon is to be administered to a induced persisting amnestic disorder, mild cognitive impair patient in a daily dose ranging between 5 and 15 mg of the ment disorder and other cognitive disorders. active ingredient. The present invention thus relates to the use of pipamperon According to a preferred embodiment, the invention relates or a pharmaceutically acceptable salt thereof for the prepara 60 to the use as described above, wherein said COX-2 inhibitor tion of a medicament for treating the underlying emotion compound is chosen from the group consisting of valdecoxib, dysregulation of a cognitive mental disease or disorder rofecoxib, parecoxib, etoricoxib, COX 189, celecoxib and selected from the group of diseases and disorders consisting ABT-963, preferably parecoxib, etoricoxib or COX 189, or a of Alzheimer Disease, Substance-induced persisting demen pro-drug or an active metabolite thereof, or a pharmaceuti tia, Vascular dementia, dementia due to HIV disease, demen 65 cally acceptable salt thereof. Preferably, parecoxib is to be tia due to head trauma, dementia due to Parkinson Disease, administered in a daily dose of between 20 and 80 mg of the dementia due to Huntington Disease, dementia due to Pick active ingredient. Preferably, etoricoxib is to be administered US 8,304,431 B2 39 40 in a daily dose of between 20 and 120 mg of the active The invention also relates to a pharmaceutical composition ingredient. Preferably, COX 189 is to be administered in a as described above wherein pipamperon is provided in a daily dose of between 100 and 800 mg of the active ingredi unitary dose of between 5 and 15 mg of the active ingredient ent. and wherein said COX-inhibiting nitric oxide donator (CI The invention also relates to a pharmaceutical composition NOD) is AZD3582, preferably provided in a unitary dose of comprising (a) pipamperon, and (b) a COX-2 inhibitor, pref between 93.75 and 750 mg of the active ingredient. erably chosen from the group consisting of Valdecoxib, rofe 26: Combination Therapy with a CRF1 (Corticoid-Releasing coxib, parecoxib, etoricoxib, COX 189, celecoxib and ABT Factor Receptor 1) Antagonist 963, preferably parecoxib, etoricoxib or COX 189, or a pro The mental disorders which can be treated using com drug or an active metabolite thereof, or a pharmaceutically 10 pounds having a high selective affinity for the 5-HT2A and acceptable salt thereof, as a combined preparation for simul D4 receptor, for instance pipamperon, in a combination taneous, separate or sequential use for treating the underlying therapy with a CRF1 (Corticotropin-Releasing Factor recep emotion dysregulation of pain disorders. tor 1) antagonist, are chosen from the group of diseases or The invention also relates to a pharmaceutical composition disorders consisting of mood disorders, anxiety disorders, as described above wherein pipamperon is provided in a 15 eating disorders, premenstrual syndrome, Somatoform disor unitary dose of between 5 and 15 mg of the active ingredient ders (excluding pain disorders), factitious disorders, disso and wherein said COX-2 inhibitor is parecoxib, preferably ciative disorders, sexual and gender identity disorders, sleep provided in a unitary dose of between 20 and 80 mg of the disorders, adjustment disorders, impulse control disorders, active ingredient. Substance related disorders, personality disorders, bereave The invention also relates to a pharmaceutical composition ment, occupational problem, problems related to abuse or as described above wherein pipamperon is provided in a neglect and pain disorders. unitary dose of between 5 and 15 mg of the active ingredient The present invention thus relates to the use of pipamperon and wherein said COX-2 inhibitor is etoricoxib, preferably or a pharmaceutically acceptable salt thereof for the prepara provided in a unitary dose of between 20 and 120 mg of the tion of a medicament for treating the underlying emotion active ingredient. 25 dysregulation of a non-cognitive mental disease or disorder The invention also relates to a pharmaceutical composition selected from the group of diseases and disorders consisting as described above wherein pipamperon is provided in a of mood disorders, anxiety disorders, eating disorders, pre unitary dose of between 5 and 15 mg of the active ingredient menstrual syndrome, Somatoform disorders (excluding pain and wherein said COX-2 inhibitors COX 189, preferably disorders), factitious disorders, dissociative disorders, sexual provided in a unitary dose of between 100 and 800 mg of the 30 and gender identity disorders, sleep disorders, adjustment active ingredient. disorders, impulse control disorders, Substance related disor 25: Combination Therapy with a COX-Inhibiting Nitric ders, personality disorders, bereavement, occupational prob Oxide Donator (CINOD) Compound lemand problems related to abuse or neglect, characterized in The mental disorders which can be treated using com that pipamperon or said pharmaceutically acceptable salt pounds having a high selective affinity for the 5-HT2A and 35 thereof is administered simultaneously with, separate from or D4 receptor, for instance pipamperon, in a combination prior to the administration of a CRF1 antagonist compound to therapy with a COX-inhibiting nitric oxide donator (CINOD) augment the therapeutic effect or to provide a faster onset of compound, are pain disorders. the therapeutic effect of said CRF1 antagonist compound, The present invention thus relates to the use of pipamperon further characterized in that pipamperon is to be administered or a pharmaceutically acceptable salt thereof for the prepara 40 to a patientina daily dose ranging between 5 and 15 mg of the tion of a medicament for treating the underlying emotion active ingredient. dysregulation of pain disorders, characterized in that pipam The present invention thus relates to the use of pipamperon peron or said pharmaceutically acceptable salt thereof is or a pharmaceutically acceptable salt thereof for the prepara administered simultaneously with, separate from or prior to tion of a medicament for treating the underlying emotion the administration of a COX-inhibiting nitric oxide donator 45 dysregulation of pain disorders, characterized in that pipam (CINOD) compound to augment the therapeutic effect or to peron or said pharmaceutically acceptable salt thereof is provide a faster onset of the therapeutic effect of said COX administered simultaneously with, separate from or prior to inhibiting nitric oxide donator (CINOD) compound, further the administration of a CRF1 antagonist compound to aug characterized in that pipamperon is to be administered to a ment the therapeutic effect or to provide a faster onset of the patient in a daily dose ranging between 5 and 15 mg of the 50 therapeutic effect of said CRF1 antagonist compound, further active ingredient. characterized in that pipamperon is to be administered to a According to a preferred embodiment, the invention relates patient in a daily dose ranging between 5 and 15 mg of the to the use as described above, wherein said COX-inhibiting active ingredient. nitric oxide donator (CINOD) compound is chosen from the According to a preferred embodiment, the invention relates group consisting of AZD4717 and AZD3582 or a pro-drug or 55 to the uses as described above, wherein said CRF1 antagonist an active metabolite thereof, or a pharmaceutically accept compound is chosen from the group consisting of R121919, able salt thereof. Preferably, AZD3582 is to be administered NBI-34041, elzasonan, CP-448,187, CP-154-526, AAG 561 in a daily dose ranging between 93.75 and 750 mg of the and 723620, preferably 8121919, elzasonan or AAG 561, or a active ingredient. pro-drug or an active metabolite thereof, or a pharmaceuti The invention also relates to a pharmaceutical composition 60 cally acceptable salt thereof. Preferably, R121919 is to be comprising (a) pipamperon, and (b) a COX-inhibiting nitric administered in a daily dose of between 5 and 80 mg of the oxide donator (CINOD), preferably chosen from the group active ingredient. consisting of AZD4717 and AZD3582 or a pro-drug or an The invention also relates to a pharmaceutical composition active metabolite thereof, or a pharmaceutically acceptable comprising (a) pipamperon, and (b) a CRF1 antagonist, pref salt thereof, as a combined preparation for simultaneous, 65 erably chosen from the group consisting of R121919, NBI separate or sequential use for treating the underlying emotion 34041, elzasonan, CP-448,187, CP-154-526, AAG 561 and dysregulation of pain disorders. 723620, preferably R121919, elzasonan or AAG 561, or a US 8,304,431 B2 41 42 pro-drug or an active metabolite thereof, or a pharmaceuti 28: Combination Therapy with D2 (Dopamine 2) Receptor cally acceptable salt thereof, as a combined preparation for Antagonist simultaneous, separate or sequential use for treating the The mental disorders which can be treated using com underlying emotion dysregulation of a mental disease or dis pounds having a high selective affinity for the 5-HT2A and D4 receptor, for instance pipamperon, in a combination order which is chosen from the group of diseases or disorders therapy with D2 (dopamine 2) receptorantagonist, are chosen consisting of mood disorders, anxiety disorders, eating dis from the group of diseases or disorders consisting of mood orders, premenstrual syndrome, Somatoform disorders (ex disorders, psychotic disorders, Somatoform disorders (ex cluding pain disorders), factitious disorders, dissociative dis cluding pain disorders), factitious disorders, dissociative dis orders, sexual and gender identity disorders, sleep disorders, orders, sleep disorders, adjustment disorders, impulse control adjustment disorders, impulse control disorders, Substance 10 disorders, pervasive development disorders, disruptive related disorders, personality disorders, bereavement, occu behaviour disorders, Substance-related disorders, personality pational problem, problems related to abuse or neglect and disorders, psychological factors affecting medical condi pain disorders. tions, malingering, antisocial behaviour, bereavement, occu The invention also relates to a pharmaceutical composition pational problem, identity problem, problems related to abuse 15 or neglect, pain disorders and delirium. as described above wherein pipamperon is provided in a The present invention thus relates to the use of pipamperon unitary dose of between 5 and 15 mg of the active ingredient or a pharmaceutically acceptable salt thereof for the prepara and wherein said CRF1 antagonist is R121919, preferably tion of a medicament for treating the underlying emotion provided in a unitary dose of between 5 and 80 mg of the dysregulation of a non-cognitive mental disease or disorder active ingredient. selected from the group of diseases and disorders consisting 27: Combination Therapy with a D1 (Dopamine 1) Receptor mood disorders, psychotic disorders, somatoform disorders Agonist (excluding pain disorders), factitious disorders, dissociative The mental disorders which can be treated using com disorders, sleep disorders, adjustment disorders, impulse pounds having a high selective affinity for the 5-HT2A and control disorders, pervasive development disorders, disrup D4 receptor, for instance pipamperon, in a combination 25 tive behaviour disorders, substance-related disorders, person therapy with a D1 (dopamine 1) receptoragonist, are chosen ality disorders, psychological factors affecting medical con from the group of diseases or disorders consisting of Sub ditions, malingering, antisocial behaviour, bereavement, stance related disorders and Parkinson disease. occupational problem, identity problem and problems related The present invention thus relates to the use of pipamperon to abuse or neglect, characterized in that pipamperon or said or a pharmaceutically acceptable salt thereof for the prepara 30 pharmaceutically acceptable salt thereof is administered simultaneously with, separate from or prior to the adminis tion of a medicament for treating the underlying emotion tration of a D2 receptor antagonist compound to augment the dysregulation of substance related disorders, characterized in therapeutic effect or to provide a faster onset of the therapeu that pipamperon or said pharmaceutically acceptable salt tic effect of said D2 receptor antagonist compound, further thereof is administered simultaneously with, separate from or 35 characterized in that pipamperon is to be administered to a prior to the administration of a D1 receptoragonist compound patient in a daily dose ranging between 5 and 15 mg of the to augment the therapeutic effect or to provide a faster onset active ingredient. of the therapeutic effect of said D1 receptor agonist com The present invention thus relates to the use of pipamperon pound, further characterized in that pipamperon is to be or a pharmaceutically acceptable salt thereof for the prepara administered to a patient in a daily dose ranging between 5 40 tion of a medicament for treating the underlying emotion and 15 mg of the active ingredient. dysregulation of pain disorders, characterized in that pipam The present invention thus relates to the use of pipamperon peron or said pharmaceutically acceptable salt thereof is or a pharmaceutically acceptable salt thereof for the prepara administered simultaneously with, separate from or prior to tion of a medicament for treating the underlying emotion the administration of a D2 receptor antagonist compound to dysregulation of Parkinson disease, characterized in that 45 augment the therapeutic effect or to provide a faster onset of pipamperon or said pharmaceutically acceptable salt thereof the therapeutic effect of said D2 receptor antagonist com is administered simultaneously with, separate from or prior to pound, further characterized in that pipamperon is to be the administration of a D1 receptor agonist compound to administered to a patient in a daily dose ranging between 5 augment the therapeutic effect or to provide a faster onset of and 15 mg of the active ingredient. the therapeutic effect of said D1 receptor agonist compound, 50 The present invention thus relates to the use of pipamperon further characterized in that pipamperon is to be administered or a pharmaceutically acceptable salt thereof for the prepara to a patientina daily dose ranging between 5 and 15 mg of the tion of a medicament for treating the underlying emotion active ingredient. dysregulation of delirium, characterized in that pipamperon According to a preferred embodiment, the invention relates or said pharmaceutically acceptable salt thereof is adminis to the uses as described above, wherein said D1 receptor 55 tered simultaneously with, separate from or prior to the agonist compound is DAS-431 or a pro-drug or an active administration of a D2 receptor antagonist compound to aug metabolite thereof, or a pharmaceutically acceptable salt ment the therapeutic effect or to provide a faster onset of the thereof. therapeutic effect of said D2 receptor antagonist compound, The invention also relates to a pharmaceutical composition further characterized in that pipamperon is to be administered comprising (a) pipamperon, and (b) a D1 receptor agonist, 60 to a patientina daily dose ranging between 5 and 15 mg of the preferably DAS-431 or a pro-drug or an active metabolite active ingredient. thereof, or a pharmaceutically acceptable salt thereof, as a According to a preferred embodiment, the invention relates combined preparation for simultaneous, separate or sequen to the uses as described above, wherein said D2 receptor tial use for treating the underlying emotion dysregulation of a antagonist compound is chosen from the group consisting of mental disease or disorder which is chosen from the group of 65 and , preferably bifeprunoX, or a pro diseases or disorders consisting of Substance related disorders drug or an active metabolite thereof, or a pharmaceutically and Parkinson disease. acceptable salt thereof. US 8,304,431 B2 43 44 The invention also relates to a pharmaceutical composition The present invention thus relates to the use of pipamperon comprising (a) pipamperon, and (b) a D2 receptor antagonist, or a pharmaceutically acceptable salt thereof for the prepara preferably chosen from the group consisting of bifeprunoX tion of a medicament for treating the underlying emotion and amisulpride, preferably bifeprunoX, or a pro-drug or an dysregulation of delirium, characterized in that pipamperon active metabolite thereof, or a pharmaceutically acceptable or said pharmaceutically acceptable salt thereof is adminis salt thereof, as a combined preparation for simultaneous, tered simultaneously with, separate from or prior to the separate or sequential use for treating the underlying emotion administration of a D3 receptor antagonist compound to aug dysregulation of a mental disease or disorder which is chosen ment the therapeutic effect or to provide a faster onset of the from the group of diseases or disorders consisting of mood therapeutic effect of said D3 receptor antagonist compound, disorders, psychotic disorders, somatoform disorders (ex 10 cluding pain disorders), factitious disorders, dissociative dis further characterized in that pipamperon is to be administered orders, sleep disorders, adjustment disorders, impulse control to a patientina daily dose ranging between 5 and 15 mg of the disorders, pervasive development disorders, disruptive active ingredient. behaviour disorders, Substance-related disorders, personality The present invention thus relates to the use of pipamperon disorders, psychological factors affecting medical condi 15 or a pharmaceutically acceptable salt thereof for the prepara tions, malingering, antisocial behaviour, bereavement, occu tion of a medicament for treating the underlying emotion pational problem, identity problem, problems related to abuse dysregulation of Parkinson disease, characterized in that or neglect, pain disorders and delirium. pipamperon or said pharmaceutically acceptable salt thereof 29: Combination Therapy with D3 (Dopamine 3) Receptor is administered simultaneously with, separate from or prior to Antagonist the administration of a D3 receptor agonist compound to The mental disorders which can be treated using com augment the therapeutic effect or to provide a faster onset of pounds having a high selective affinity for the 5-HT2A and the therapeutic effect of said D3 receptoragonist compound, D4 receptor, for instance pipamperon, in a combination further characterized in that pipamperon is to be administered therapy with D3 (dopamine 3) receptor antagonist, are chosen to a patientina daily dose ranging between 5 and 15 mg of the from the group of diseases or disorders consisting of psy 25 active ingredient. chotic disorders, Somatoform disorders (excluding pain dis According to a preferred embodiment, the invention relates orders), factitious disorders, dissociative disorders, sleep dis to the uses as described above, wherein said D3 receptor orders, adjustment disorders, impulse control disorders, antagonist compound is chosen from the group consisting of pervasive development disorders, disruptive behaviour disor BSF-201640 and PD 58491, or a pro-drug or an active ders, Substance-related disorders, personality disorders, psy 30 metabolite thereof, or a pharmaceutically acceptable salt chological factors affecting medical conditions, malingering, thereof. antisocial behaviour, bereavement, occupational problem, The invention also relates to a pharmaceutical composition identity problem, problems related to abuse or neglect, pain comprising (a) pipamperon, and (b) a D3 receptor antagonist, disorders, delirium and Parkinson disease. preferably chosen from the group consisting of BSF-201640 The present invention thus relates to the use of pipamperon 35 and PD 58491, or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof for the prepara or a pharmaceutically acceptable salt thereof, as a combined tion of a medicament for treating the underlying emotion preparation for simultaneous, separate or sequential use for dysregulation of a non-cognitive mental disease or disorder treating the underlying emotion dysregulation of a mental selected from the group of diseases and disorders consisting disease or disorder which is chosen from the group of diseases of psychotic disorders. Somatoform disorders (excluding pain 40 or disorders consisting of psychotic disorders, somatoform disorders), factitious disorders, dissociative disorders, sleep disorders (excluding pain disorders), factitious disorders, dis disorders, adjustment disorders, impulse control disorders, Sociative disorders, sleep disorders, adjustment disorders, pervasive development disorders, disruptive behaviour disor impulse control disorders, pervasive development disorders, ders, Substance-related disorders, personality disorders, psy disruptive behaviour disorders, substance-related disorders, chological factors affecting medical conditions, malingering, 45 personality disorders, psychological factors affecting medi antisocial behaviour, bereavement, occupational problem, cal conditions, malingering, antisocial behaviour, bereave identity problem, problems related to abuse or neglect, char ment, occupational problem, identity problem, problems acterized in that pipamperon or said pharmaceutically accept related to abuse or neglect, pain disorders, delirium and Par able salt thereof is administered simultaneously with, sepa kinson disease. rate from or prior to the administration of a D3 receptor 50 30: Combination Therapy with a DA (Dopamine) Uptake antagonist compound to augment the therapeutic effect or to Inhibitor provide a faster onset of the therapeutic effect of said D3 The mental disorders which can be treated using com receptor antagonist compound, further characterized in that pounds having a high selective affinity for the 5-HT2A and pipamperon is to be administered to a patient in a daily dose D4 receptor, for instance pipamperon, in a combination ranging between 5 and 15 mg of the active ingredient. 55 therapy with a DA (dopamine) uptake inhibitor, are chosen The present invention thus relates to the use of pipamperon from the group of diseases or disorders consisting of Sub or a pharmaceutically acceptable salt thereof for the prepara stance related disorders and Parkinson disease. tion of a medicament for treating the underlying emotion The present invention thus relates to the use of pipamperon dysregulation of pain disorders, characterized in that pipam or a pharmaceutically acceptable salt thereof for the prepara peron or said pharmaceutically acceptable salt thereof is 60 tion of a medicament for treating the underlying emotion administered simultaneously with, separate from or prior to dysregulation of substance related disorders, characterized in the administration of a D3 receptor antagonist compound to that pipamperon or said pharmaceutically acceptable salt augment the therapeutic effect or to provide a faster onset of thereof is administered simultaneously with, separate from or the therapeutic effect of said D3 receptor antagonist com prior to the administration of a DA uptake inhibitor com pound, further characterized in that pipamperon is to be 65 pound to augment the therapeutic effect or to provide a faster administered to a patient in a daily dose ranging between 5 onset of the therapeutic effect of said DA uptake inhibitor and 15 mg of the active ingredient. compound, further characterized in that pipamperon is to be US 8,304,431 B2 45 46 administered to a patient in a daily dose ranging between 5 peron or said pharmaceutically acceptable salt thereof is and 15 mg of the active ingredient. administered simultaneously with, separate from or prior to The present invention thus relates to the use of pipamperon the administration of a dopamine (receptor) agonist com or a pharmaceutically acceptable salt thereof for the prepara pound to augment the therapeutic effect or to provide a faster tion of a medicament for treating the underlying emotion 5 onset of the therapeutic effect of said dopamine (receptor) dysregulation of Parkinson disease, characterized in that agonist compound, further characterized in that pipamperon pipamperon or said pharmaceutically acceptable salt thereof is to be administered to a patient in a daily dose ranging is administered simultaneously with, separate from or prior to between 5 and 15 mg of the active ingredient. the administration of a DA uptake inhibitor compound to The present invention thus relates to the use of pipamperon augment the therapeutic effect or to provide a faster onset of 10 the therapeutic effect of said DA uptake inhibitor compound, or a pharmaceutically acceptable salt thereof for the prepara further characterized in that pipamperon is to be administered tion of a medicament for treating the underlying emotion to a patientina daily dose ranging between 5 and 15 mg of the dysregulation of Parkinson disease, characterized in that active ingredient. pipamperon or said pharmaceutically acceptable salt thereof According to a preferred embodiment, the invention relates 15 is administered simultaneously with, separate from or prior to to the uses as described above, wherein said DA uptake the administration of a dopamine (receptor) agonist com inhibitor compound is chosen from the group consisting of pound to augment the therapeutic effect or to provide a faster safinamide and GBR 12909, or a pro-drug or an active onset of the therapeutic effect of said dopamine (receptor) metabolite thereof, or a pharmaceutically acceptable salt agonist compound, further characterized in that pipamperon thereof. is to be administered to a patient in a daily dose ranging The invention also relates to a pharmaceutical composition between 5 and 15 mg of the active ingredient. comprising (a) pipamperon, and (b) a D2 receptor antagonist, According to a preferred embodiment, the invention relates preferably chosen from the group consisting of Safinamide to the uses as described above, wherein said dopamine (recep and GBR 12909, or a pro-drug oran active metabolite thereof, tor) agonist compound is chosen from the group consisting of or a pharmaceutically acceptable salt thereof, as a combined 25 Sumanirole, SLV 308, sarizotan, S32504, (prefer preparation for simultaneous, separate or sequential use for ably a Once-a-Day Transdermal Patch), ropinirole HCL treating the underlying emotion dysregulation of a mental (preferably controlled-release formulation), pramipexole, disease or disorder which is chosen from the group of diseases DAB452, , , alaptide, cabergoline, or disorders consisting of Substance related disorders and , preferably Sumanirole, rotigotine (preferably a Parkinson disease. 30 31: Combination Therapy with an Dopamine (Receptor) Once-a-Day Transdermal Patch), or ropinirole Agonist HCL (preferably controlled-release formulation), or a pro The mental disorders which can be treated using com drug or an active metabolite thereof, or a pharmaceutically pounds having a high selective affinity for the 5-HT2A and acceptable salt thereof. Preferably, Sumanirole is to be admin D4 receptor, for instance pipamperon, in a combination 35 istered in a daily dose of between 4 and 16 mg of the active therapy with an dopamine (receptor) agonist, are chosen from ingredient. Preferably, rotigotine (Once-a-Day Transdermal the group of diseases or disorders consisting of mood disor Patch) is to be administered in a daily dose of between 4.5 and ders, anxiety disorders, eating disorders, premenstrual Syn 13.5 mg of the active ingredient. Preferably, ropinirole HCL drome. Somatoform disorders (excluding pain disorders), fac (controlled-release formulation) is to be administered in a titious disorders, dissociative disorders, adjustment 40 daily dose of between 0.75 and 24 mg of the active ingredient. disorders, impulse control disorders, attention-deficit disor Preferably, pergolide is to be administered in a daily dose of ders, Substance-related disorders, personality disorders, between 0.5 and 10 mg of the active ingredient. problems related to abuse or neglect, pain disorders and Par The invention also relates to a pharmaceutical composition kinson disease. comprising (a) pipamperon, and (b) a dopamine (receptor) The present invention thus relates to the use of pipamperon 45 agonist, preferably chosen from the group consisting of or a pharmaceutically acceptable salt thereof for the prepara Sumanirole, SLV 308, sarizotan, S32504, rotigotine (prefer tion of a medicament for treating the underlying emotion ably a Once-a-Day Transdermal Patch), ropinirole HCL dysregulation of a non-cognitive mental disease or disorder (preferably controlled-release formulation), pramipexole, selected from the group of diseases and disorders consisting DAB452, cabergoline, bromocriptine, alaptide, cabergoline, mood disorders, anxiety disorders, eating disorders, premen 50 lisuride and pergolide, more preferably Sumanirole, rotigo strual syndrome, Somatoform disorders (excluding pain dis tine (preferably a Once-a-Day Transdermal Patch), ropinirole orders), factitious disorders, dissociative disorders, adjust HCL (preferably controlled-release formulation) or per ment disorders, impulse control disorders, attention-deficit golide, or a pro-drug or an active metabolite thereof, or a disorders, Substance-related disorders, personality disorders pharmaceutically acceptable salt thereof, as a combined and problems related to abuse or neglect, characterized in that 55 preparation for simultaneous, separate or sequential use for pipamperon or said pharmaceutically acceptable salt thereof treating the underlying emotion dysregulation of a mental is administered simultaneously with, separate from or prior to disease or disorder which is chosen from the group of diseases the administration of a dopamine (receptor) agonist com or disorders consisting of mood disorders, anxiety disorders, pound to augment the therapeutic effect or to provide a faster eating disorders, premenstrual syndrome, Somatoform disor onset of the therapeutic effect of said dopamine (receptor) 60 ders (excluding pain disorders), factitious disorders, disso agonist compound, further characterized in that pipamperon ciative disorders, adjustment disorders, impulse control dis is to be administered to a patient in a daily dose ranging orders, attention-deficit disorders, Substance-related between 5 and 15 mg of the active ingredient. disorders, personality disorders, problems related to abuse or The present invention thus relates to the use of pipamperon neglect, pain disorders and Parkinson disease. or a pharmaceutically acceptable salt thereof for the prepara 65 The invention also relates to a pharmaceutical composition tion of a medicament for treating the underlying emotion as described above wherein pipamperon is provided in a dysregulation of pain disorders, characterized in that pipam unitary dose of between 5 and 15 mg of the active ingredient US 8,304,431 B2 47 48 and wherein said dopamine (receptor) agonist is Sumanirole, maceutically acceptable salt thereof. Preferably, CPI-1189 is preferably provided in a unitary dose of between 4 and 16 mg to be administered in a daily dose of between 50 and 100 mg of the active ingredient. of the active ingredient. The invention also relates to a pharmaceutical composition The invention also relates to a pharmaceutical composition as described above wherein pipamperon is provided in a comprising (a) pipamperon, and (b) a compound that acti unitary dose of between 5 and 15 mg of the active ingredient vates ERK (extracellular signal-related kinase), preferably and wherein said dopamine (receptor) agonist is rotigotine CPI-1189 or a pro-drug or an active metabolite thereof, or a (Once-a-Day Transdermal Patch), preferably provided in a pharmaceutically acceptable salt thereof, as a combined unitary dose of between 4.5 and 13.5 mg of the active ingre preparation for simultaneous, separate or sequential use for dient. 10 treating the underlying emotion dysregulation of a mental disease or disorder which is chosen from the group of diseases The invention also relates to a pharmaceutical composition or disorders consisting of Alzheimer Disease, Substance-in as described above wherein pipamperon is provided in a duced persisting dementia, Vascular dementia, dementia due unitary dose of between 5 and 15 mg of the active ingredient to HIV disease, dementia due to head trauma, dementia due to and wherein said dopamine (receptor) agonist is ropinirole 15 Parkinson Disease, dementia due to Huntington Disease, HCL (controlled-release formulation), preferably provided in dementia due to Pick Disease, dementia due to Creutzfeldt a unitary dose of between 0.75 and 24 mg of the active Jacob Disease, amnestic disorders due to a general medical ingredient. condition, Substance-induced persisting amnestic disorder, The invention also relates to a pharmaceutical composition mild cognitive impairment disorder and other cognitive dis as described above wherein pipamperon is provided in a orders. unitary dose of between 5 and 15 mg of the active ingredient The invention also relates to a pharmaceutical composition and wherein said dopamine (receptor) agonist is pergolide, as described above wherein pipamperon is provided in a preferably provided in a unitary dose of between 0.5 and 10 unitary dose of between 5 and 15 mg of the active ingredient mg of the active ingredient. and wherein said compound that activates ERK (extracellular 32: Combination Therapy with a Compound Activating ERK 25 signal-related kinase) is CPI-1189, preferably provided in a (Extracellular Signal-Related Kinase) unitary dose of between 50 and 100 mg of the active ingredi The mental disorders which can be treated using com ent. pounds having a high selective affinity for the 5-HT2A and 33: Combination Therapy with a GABA (Gamma-Aminobu D4 receptor, for instance pipamperon, in a combination tyric Acid) Agonist Compound 30 The mental disorders which can be treated using com therapy with a compound that activates ERK (extracellular pounds having a high selective affinity for the 5-HT2A and signal-related kinase), are chosen from the group of diseases D4 receptor, for instance pipamperon, in a combination or disorders consisting of Alzheimer Disease, Substance-in therapy with a GABA (gamma-aminobutyric acid) agonist duced persisting dementia, Vascular dementia, dementia due compound, are chosen from the group of diseases or disorders to HIV disease, dementia due to head trauma, dementia due to 35 consisting of Alzheimer Disease, Substance-induced persist Parkinson Disease, dementia due to Huntington Disease, ing dementia, Vascular dementia, dementia due to HIV dis dementia due to Pick Disease, dementia due to Creutzfeldt ease, dementia due to head trauma, dementia due to Parkinson Jacob Disease, amnestic disorders due to a general medical Disease, dementia due to Huntington Disease, dementia due condition, Substance-induced persisting amnestic disorder, to Pick Disease, dementia due to Creutzfeldt-Jacob Disease, mild cognitive impairment disorder and other cognitive dis 40 amnestic disorders due to a general medical condition, Sub orders. stance-induced persisting amnestic disorder, mild cognitive The present invention thus relates to the use of pipamperon impairment disorder and other cognitive disorders. or a pharmaceutically acceptable salt thereof for the prepara The present invention thus relates to the use of pipamperon tion of a medicament for treating the underlying emotion or a pharmaceutically acceptable salt thereof for the prepara dysregulation of a cognitive mental disease or disorder 45 tion of a medicament for treating the underlying emotion selected from the group of diseases and disorders consisting dysregulation of a cognitive mental disease or disorder of Alzheimer Disease, Substance-induced persisting demen selected from the group of diseases and disorders consisting tia, Vascular dementia, dementia due to HIV disease, demen of Alzheimer Disease, Substance-induced persisting demen tia due to head trauma, dementia due to Parkinson Disease, tia, Vascular dementia, dementia due to HIV disease, demen dementia due to Huntington Disease, dementia due to Pick 50 tia due to head trauma, dementia due to Parkinson Disease, Disease, dementia due to Creutzfeldt-Jacob Disease, amnes dementia due to Huntington Disease, dementia due to Pick tic disorders due to a general medical condition, Substance Disease, dementia due to Creutzfeldt-Jacob Disease, amnes induced persisting amnestic disorder, mild cognitive impair tic disorders due to a general medical condition, Substance ment disorder and other cognitive disorders, characterized in induced persisting amnestic disorder, mild cognitive impair that pipamperon or said pharmaceutically acceptable salt 55 ment disorder and other cognitive disorders, characterized in thereof is administered simultaneously with, separate from or that pipamperon or said pharmaceutically acceptable salt prior to the administration of a compound that activates ERK thereof is administered simultaneously with, separate from or (extracellular signal-related kinase) to augment the therapeu prior to the administration of a GABA agonist compound to tic effect or to provide a faster onset of the therapeutic effect augment the therapeutic effect or to provide a faster onset of of said compound that activates ERK (extracellular signal 60 the therapeutic effect of said GABA agonist compound, fur related kinase), further characterized in that pipamperon is to ther characterized in that pipamperon is to be administered to be administered to a patient in a daily dose ranging between 5 a patient in a daily dose ranging between 5 and 15 mg of the and 15 mg of the active ingredient. active ingredient. According to a preferred embodiment, the invention relates According to a preferred embodiment, the invention relates to the use as described above, wherein said compound that 65 to the use as described above, wherein said GABA agonist activates ERK (extracellular signal-related kinase) is CPI compound is nefiracetam or a pro-drug or an active metabo 1189 or a pro-drug or an active metabolite thereof, or a phar lite thereof, or a pharmaceutically acceptable salt thereof. US 8,304,431 B2 49 50 The invention also relates to a pharmaceutical composition Sonality disorders, bereavement, occupational problem and comprising (a) pipamperon, and (b) a GABA agonist, prefer problems related to abuse or neglect. ably nefiracetamora pro-drug oran active metabolite thereof, The present invention thus relates to the use of pipamperon or a pharmaceutically acceptable salt thereof, as a combined or a pharmaceutically acceptable salt thereof for the prepara preparation for simultaneous, separate or sequential use for 5 tion of a medicament for treating the underlying emotion treating the underlying emotion dysregulation of a mental dysregulation of a non-cognitive mental disease or disorder disease or disorder which is chosen from the group of diseases selected from the group of diseases and disorders consisting or disorders consisting of Alzheimer Disease, Substance-in of anxiety disorders, eating disorders, premenstrual Syn duced persisting dementia, Vascular dementia, dementia due drome. Somatoform disorders (excluding pain disorders), fac 10 titious disorders, dissociative disorders, sexual and gender to HIV disease, dementia due to head trauma, dementia due to identity disorders, sleep disorders, adjustment disorders, Parkinson Disease, dementia due to Huntington Disease, impulse control disorders, personality disorders, bereave dementia due to Pick Disease, dementia due to Creutzfeldt ment, occupational problem and problems related to abuse or Jacob Disease, amnestic disorders due to a general medical neglect, characterized in that pipamperon or said pharmaceu condition, Substance-induced persisting amnestic disorder, 15 tically acceptable salt thereof is administered simultaneously mild cognitive impairment disorder and other cognitive dis with, separate from or prior to the administration of a orders. GABA-A modulator compound to augment the therapeutic 34: Combination Therapy with a GABA-A Agonist Com effect or to provide a faster onset of the therapeutic effect of pound said GABA-A modulator compound, further characterized in The mental disorders which can be treated using com- 20 that pipamperon is to be administered to a patient in a daily pounds having a high selective affinity for the 5-HT2A and dose ranging between 5 and 15 mg of the active ingredient. D4 receptor, for instance pipamperon, in a combination According to a preferred embodiment, the invention relates therapy with a GABA-A (gamma-aminobutyric acid receptor to the use as described above, wherein said GABA-A modu A) agonist compound, are sleep disorders. lator compound is chosen from the group consisting of Zolpi The present invention thus relates to the use of pipamperon 25 dem (preferably MR sustained-release version), Zaleplon or a pharmaceutically acceptable salt thereof for the prepara (preferably extended-release formulation), SL 65.1498, tion of a medicament for treating the underlying emotion SEP174559, pagoclone. NGD 96-3, indiplon, esZopiclone, dysregulation of sleep disorders, characterized in that pipam CP-730,330 (NGD 96-3)andocinaplon, preferably Zolpidem peron or said pharmaceutically acceptable salt thereof is (preferably MR sustained-release version), Zaleplon (prefer administered simultaneously with, separate from or prior to 30 ably extended-release formulation), pagoclone, indiplon or the administration of a GABA-A agonist compound to aug eSZopiclone, or a pro-drug or an active metabolite thereof, or ment the therapeutic effect or to provide a faster onset of the a pharmaceutically acceptable salt thereof. Preferably, Zolpi therapeutic effect of said GABA-A agonist compound, fur dem MR Sustained-release version is to be administered in a ther characterized in that pipamperon is to be administered to daily dose of between 10 and 20 mg of the active ingredient. a patient in a daily dose ranging between 5 and 15 mg of the 35 Preferably, Zaleplon extended-release is to be administered in active ingredient. a daily dose ranging between 2.5 and 20 mg of the active According to a preferred embodiment, the invention relates ingredient. Preferably, pagoclone is to be administered in a to the use as described above, wherein said GABA-A agonist daily dose ranging between 7.5 and 60 mg of the active compound is gaboxadol or a pro-drug oran active metabolite ingredient. Preferably, indiplon is to be administered in a thereof, or a pharmaceutically acceptable salt thereof. Pref. 40 daily dose of between 10 and 20 mg of the active ingredient. erably, gaboxadol is to be administered in a daily dose of Preferably, esZopiclone is to be administered in a daily dose between 5 and 20 mg of the active ingredient. of between 2 and 3 mg of the active ingredient. Preferably, The invention also relates to a pharmaceutical composition ocinaplon is to be administered in a daily dose of between 10 comprising (a) pipamperon, and (b) an GABA-A agonist, and 60 mg of the active ingredient. preferably gaboxadol or a pro-drug or an active metabolite 45 The invention also relates to a pharmaceutical composition thereof, or a pharmaceutically acceptable salt thereof, as a comprising (a) pipamperon, and (b) a GABA-A modulator, combined preparation for simultaneous, separate or sequen preferably chosen from the group consisting of Zolpidem tial use for treating the underlying emotion dysregulation of (preferably MR sustained-release version), Zaleplon (prefer sleep disorders. ably extended-release formulation), SL 65.1498, The invention also relates to a pharmaceutical composition 50 SEP174559, pagoclone, indiplon, esZopiclone, CP-730,330 as described above wherein pipamperon is provided in a (NGD 96-3) and ocinaplon, preferably Zolpidem (preferably unitary dose of between 5 and 15 mg of the active ingredient MR sustained-release version), Zaleplon (preferably and wherein said GABA-A agonist is Gaboxadol, preferably extended-release formulation), pagoclone. NGD 96-3, provided in a unitary dose of between 5 and 20 mg of the indiplon oresZopiclone, or a pro-drug oran active metabolite active ingredient. 55 thereof, or a pharmaceutically acceptable salt thereof, as a 35: Combination Therapy with a GABA-A Modulator Com combined preparation for simultaneous, separate or sequen pound tial use for treating the underlying emotion dysregulation of a The mental disorders which can be treated using com mental disease or disorder which is chosen from the group of pounds having a high selective affinity for the 5-HT2A and diseases or disorders consisting of anxiety disorders, eating D4 receptor, for instance pipamperon, in a combination 60 disorders, premenstrual syndrome, Somatoform disorders therapy with a GABA-A (gamma-aminobutyric acid receptor (excluding pain disorders), factitious disorders, dissociative A) modulator compound, are chosen from the group of dis disorders, sexual and gender identity disorders, sleep disor eases or disorders consisting of anxiety disorders, eating dis ders, adjustment disorders, impulse control disorders, per orders, premenstrual syndrome, Somatoform disorders (ex Sonality disorders, bereavement, occupational problem and cluding pain disorders), factitious disorders, dissociative 65 problems related to abuse or neglect. disorders, sexual and gender identity disorders, sleep disor The invention also relates to a pharmaceutical composition ders, adjustment disorders, impulse control disorders, per as described above wherein pipamperon is provided in a US 8,304,431 B2 51 52 unitary dose of between 5 and 15 mg of the active ingredient According to a preferred embodiment, the invention relates and wherein said GABA-A modulator is Zolpidem MR sus to the use as described above, wherein said GABA-Bantago tained-release version, preferably provided in a unitary dose nist compound is AVE 7398 or a pro-drug or an active of between 10 and 20 mg of the active ingredient. metabolite thereof, or a pharmaceutically acceptable salt The invention also relates to a pharmaceutical composition thereof. as described above wherein pipamperon is provided in a The invention also relates to a pharmaceutical composition unitary dose of between 5 and 15 mg of the active ingredient comprising (a) pipamperon, and (b) a GABA-Bantagonist, and wherein said GABA-A modulator is Zaleplon extended preferably AVE 7398 or a pro-drug or an active metabolite release, preferably provided in a unitary dose of between 2.5 thereof, or a pharmaceutically acceptable salt thereof, as a and 20 mg of the active ingredient. 10 combined preparation for simultaneous, separate or sequen The invention also relates to a pharmaceutical composition tial use for treating the underlying emotion dysregulation of a as described above wherein pipamperon is provided in a mental disease or disorder which is chosen from the group of unitary dose of between 5 and 15 mg of the active ingredient diseases or disorders consisting of anxiety disorders, eating and wherein said GABA-A modulator is Pagoclone, prefer disorders, premenstrual syndrome, Somatoform disorders ably provided in a unitary dose of between 7.5 and 60 mg of 15 (excluding pain disorders), factitious disorders, dissociative the active ingredient. disorders, sexual and gender identity disorders, sleep disor The invention also relates to a pharmaceutical composition ders, adjustment disorders, impulse control disorders, per as described above wherein pipamperon is provided in a Sonality disorders, bereavement, occupational problem and unitary dose of between 5 and 15 mg of the active ingredient problems related to abuse or neglect. and wherein said GABA-A modulator is indiplon, preferably 37: Combination Therapy with a Glial-Cell Line Derived provided in a unitary dose of between 10 and 20 mg of the Neurotrophic Factor Compound active ingredient. The mental disorder which can be treated using com The invention also relates to a pharmaceutical composition pounds having a high selective affinity for the 5-HT2A and as described above wherein pipamperon is provided in a D4 receptor, for instance pipamperon, in a combination unitary dose of between 5 and 15 mg of the active ingredient 25 therapy with a Glial-cell Line Derived Neurotrophic Factor and wherein said GABA-A modulator is eszopiclone, prefer compound, is Parkinson disease. ably provided in a unitary dose of between 2 and 3 mg of the The present invention thus relates to the use of pipamperon active ingredient. or a pharmaceutically acceptable salt thereof for the prepara The invention also relates to a pharmaceutical composition tion of a medicament for treating the underlying emotion as described above wherein pipamperon is provided in a 30 dysregulation of Parkinson disease, characterized in that unitary dose of between 5 and 15 mg of the active ingredient pipamperon or said pharmaceutically acceptable salt thereof and wherein said GABA-A modulator is ocinaplon, prefer is administered simultaneously with, separate from or prior to ably provided in a unitary dose of between 10 and 60 mg of the administration of a Glial-cell Line Derived Neurotrophic the active ingredient. Factor compound to augment the therapeutic effect or to 36: Combination Therapy with a GABA-B Antagonist Com 35 provide a faster onset of the therapeutic effect of said Glial pound cell Line. Derived Neurotrophic Factor compound, further The mental disorders which can be treated using com characterized in that pipamperon is to be administered to a pounds having a high selective affinity for the 5-HT2A and patient in a daily dose ranging between 5 and 15 mg of the D4 receptor, for instance pipamperon, in a combination active ingredient. therapy with a GABA-B (gamma-aminobutyric acid receptor 40 According to a preferred embodiment, the invention relates B) antagonist compound, are chosen from the group of dis to the use as described above, wherein said Glial-cell Line eases or disorders consisting of anxiety disorders, eating dis Derived Neurotrophic Factor compound is GDNF or a pro orders, premenstrual syndrome, Somatoform disorders (ex drug or an active metabolite thereof, or a pharmaceutically cluding pain disorders), factitious disorders, dissociative acceptable salt thereof. Preferably, GDNF is to be adminis disorders, sexual and gender identity disorders, sleep disor 45 tered in a daily dose ranging between 3.75 and 30 mg of the ders, adjustment disorders, impulse control disorders, per active ingredient. Sonality disorders, bereavement, occupational problem and The invention also relates to a pharmaceutical composition problems related to abuse or neglect. comprising (a) pipamperon, and (b) a Glial-cell Line Derived The present invention thus relates to the use of pipamperon Neurotrophic Factor, preferably GDNF or a pro-drug or an or a pharmaceutically acceptable salt thereof for the prepara 50 active metabolite thereof, or a pharmaceutically acceptable tion of a medicament for treating the underlying emotion salt thereof, as a combined preparation for simultaneous, dysregulation of a non-cognitive mental disease or disorder separate or sequential use for treating the underlying emotion selected from the group of diseases and disorders consisting dysregulation of Parkinson disease. of anxiety disorders, eating disorders, premenstrual Syn The invention also relates to a pharmaceutical composition drome. Somatoform disorders (excluding pain disorders), fac 55 as described above wherein pipamperon is provided in a titious disorders, dissociative disorders, sexual and gender unitary dose of between 5 and 15 mg of the active ingredient identity disorders, sleep disorders, adjustment disorders, and wherein said Glial-cell Line Derived Neurotrophic Factor impulse control disorders, personality disorders, bereave is GDNF, preferably provided in a unitary dose of between ment, occupational problem and problems related to abuse or 3.75 and 30 mg of the active ingredient. neglect, characterized in that pipamperon or said pharmaceu 60 38: Combination Therapy with a Glucocorticoid Synthesis tically acceptable salt thereof is administered simultaneously Inhibitor Compound with, separate from or prior to the administration of a The mental disorders which can be treated using com GABA-B antagonist compound to augment the therapeutic pounds having a high selective affinity for the 5-HT2A and effect or to provide a faster onset of the therapeutic effect of D4 receptor, for instance pipamperon, in a combination said GABA-Bantagonist compound, further characterized in 65 therapy with a glucocorticoid synthesis inhibitor compound, that pipamperon is to be administered to a patient in a daily are chosen from the group of diseases or disorders consisting dose ranging between 5 and 15 mg of the active ingredient. of substance related disorders and Parkinson disease. US 8,304,431 B2 53 54 The present invention thus relates to the use of pipamperon ized in that pipamperon is to be administered to a patient in a or a pharmaceutically acceptable salt thereof for the prepara daily dose ranging between 5 and 15 mg of the active ingre tion of a medicament for treating the underlying emotion dient. dysregulation of substance related disorders, characterized in The present invention thus relates to the use of pipamperon that pipamperon or said pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof for the prepara thereof is administered simultaneously with, separate from or tion of a medicament for treating the underlying emotion prior to the administration of a glucocorticoid synthesis dysregulation of pain disorders, characterized in that pipam inhibitor compound to augment the therapeutic effect or to peron or said pharmaceutically acceptable salt thereof is provide a faster onset of the therapeutic effect of said gluco administered simultaneously with, separate from or prior to corticoid synthesis inhibitor compound, further characterized 10 in that pipamperon is to be administered to a patient in a daily the administration of a glutamate receptor antagonist com dose ranging between 5 and 15 mg of the active ingredient. pound to augment the therapeutic effect or to provide a faster The present invention thus relates to the use of pipamperon onset of therapeutic effect of said glutamate receptor antago or a pharmaceutically acceptable salt thereof for the prepara nist compound, further characterized in that pipamperon is to tion of a medicament for treating the underlying emotion 15 be administered to a patient in a daily dose ranging between 5 dysregulation of Parkinson disease, characterized in that and 15 mg of the active ingredient. pipamperon or said pharmaceutically acceptable salt thereof According to a preferred embodiment, the invention relates is administered simultaneously with, separate from or prior to to the uses as described above, wherein said glutamate recep the administration of a glucocorticoid synthesis inhibitor tor antagonist compound is LY354740 or a pro-drug or an compound to augment the therapeutic effect or to provide a active metabolite thereof, or a pharmaceutically acceptable faster onset of the therapeutic effect of said glucocorticoid salt thereof. synthesis inhibitor compound, further characterized in that The invention also relates to a pharmaceutical composition pipamperon is to be administered to a patient in a daily dose comprising (a) pipamperon, and (b) a glutamate receptor ranging between 5 and 15 mg of the active ingredient. antagonist, preferably LY354740 or a pro-drug or an active According to a preferred embodiment, the invention relates 25 metabolite thereof, or a pharmaceutically acceptable salt to the uses as described above, wherein said glucocorticoid thereof, as a combined preparation for simultaneous, separate synthesis inhibitor compound is metyrapone or a pro-drug or or sequential use for treating the underlying emotion dysregu an active metabolite thereof, or a pharmaceutically accept lation of amental disease or disorder which is chosen from the able salt thereof. group of diseases or disorders consisting of anxiety disorders, The invention also relates to a pharmaceutical composition 30 comprising (a) pipamperon, and (b) a glucocorticoid synthe Somatoform disorders (excluding pain disorders), factitious sis inhibitor, preferably metyrapone or a pro-drug or an active disorders, dissociative disorders, adjustment disorders, metabolite thereof, or a pharmaceutically acceptable salt impulse control disorders, Substance-related disorders, per thereof, as a combined preparation for simultaneous, separate Sonality disorders, bereavement, occupational problem, or sequential use for treating the underlying emotion dysregu 35 problems related to abuse or neglect and pain disorders. lation of amental disease or disorder which is chosen from the 40: Combination Therapy with an GPCR (G-Protein group of diseases or disorders consisting of Substance related Coupled Receptor) Modulator disorders and Parkinson disease. The mental disorders which can be treated using com 39: Combination Therapy with a Glutamate Receptor pounds having a high selective affinity for the 5-HT2A and Antagonist Compound 40 D4 receptor, for instance pipamperon, in a combination The mental disorders which can be treated using com therapy with an GPCR (G-protein-coupled receptor) modu pounds having a high selective affinity for the 5-HT2A and lator, are chosen from the group of diseases or disorders D4 receptor, for instance pipamperon, in a combination consisting of mood disorders, anxiety disorders, eating dis therapy with a glutamate receptor antagonist compound, are orders, premenstrual syndrome, Somatoform disorders (ex chosen from the group of diseases or disorders consisting of 45 cluding pain disorders), factitious disorders, dissociative dis anxiety disorders, somatoform disorders (excluding pain dis orders, sexual and gender identity disorders, sleep disorders, orders), factitious disorders, dissociative disorders, adjust adjustment disorders, impulse control disorders, Substance ment disorders, impulse control disorders, Substance-related related disorders, personality disorders, bereavement, occu disorders, personality disorders, bereavement, occupational pational problem, problems related to abuse or neglect and problem, problems related to abuse or neglect and pain dis 50 pain disorders. orders. The present invention thus relates to the use of pipamperon The present invention thus relates to the use of pipamperon or a pharmaceutically acceptable salt thereof for the prepara or a pharmaceutically acceptable salt thereof for the prepara tion of a medicament for treating the underlying emotion tion of a medicament for treating the underlying emotion dysregulation of a non-cognitive mental disease or disorder dysregulation of a non-cognitive mental disease or disorder 55 selected from the group of diseases and disorders consisting selected from the group of diseases and disorders consisting of mood disorders, anxiety disorders, eating disorders, pre of anxiety disorders, somatoform disorders (excluding pain menstrual syndrome, Somatoform disorders (excluding pain disorders), factitious disorders, dissociative disorders, adjust disorders), factitious disorders, dissociative disorders, sexual ment disorders, impulse control disorders, Substance-related and gender identity disorders, sleep disorders, adjustment disorders, personality disorders, bereavement, occupational 60 disorders, impulse control disorders, Substance-related disor problem, and problems related to abuse or neglect, character ders, personality disorders, bereavement, occupational prob ized in that pipamperon or said pharmaceutically acceptable lemand problems related to abuse or neglect, characterized in salt thereof is administered simultaneously with, separate that pipamperon or said pharmaceutically acceptable salt from or prior to the administration of a glutamate receptor thereof is administered simultaneously with, separate from or antagonist compound to augment the therapeutic effect or to 65 prior to the administration of a GPCR modulator compound provide a faster onset of the therapeutic effect of said to augment the therapeutic effect or to provide a faster onset glutamate receptor antagonist compound, further character of the therapeutic effect of said GPCR modulator compound, US 8,304,431 B2 55 56 further characterized in that pipamperon is to be administered ther characterized in that pipamperon is to be administered to to a patientina daily dose ranging between 5 and 15 mg of the a patient in a daily dose ranging between 5 and 15 mg of the active ingredient. active ingredient. The present invention thus relates to the use of pipamperon The present invention thus relates to the use of pipamperon or a pharmaceutically acceptable salt thereof for the prepara or a pharmaceutically acceptable salt thereof for the prepara tion of a medicament for treating the underlying emotion tion of a medicament for treating the underlying emotion dysregulation of pain disorders, characterized in that pipam dysregulation of pain disorders, characterized in that pipam peron or said pharmaceutically acceptable salt thereof is peron or said pharmaceutically acceptable salt thereof is administered simultaneously with, separate from or prior to administered simultaneously with, separate from or prior to 10 the administration of a GRantagonist compound to augment the administration of a GPCR modulator compound to aug the therapeutic effect or to provide a faster onset of the thera ment the therapeutic effect or to provide a faster onset of the peutic effect of said GR antagonist compound, further char therapeutic effect of said GPCR modulator compound, fur acterized in that pipamperon is to be administered to a patient ther characterized in that pipamperon is to be administered to in a daily dose ranging between 5 and 15 mg of the active a patient in a daily dose ranging between 5 and 15 mg of the 15 ingredient. active ingredient. According to a preferred embodiment, the invention relates According to a preferred embodiment, the invention relates to the use as described above, wherein said GR antagonist to the uses as described above, wherein said GPCR modulator compound is chosen from the group consisting of ORG compound is R1204 or a pro-drug or an active metabolite 34517/34850 and mifepristone, preferably mifepristone, or a thereof, or a pharmaceutically acceptable salt thereof. pro-drug or an active metabolite thereof, or a pharmaceuti The invention also relates to a pharmaceutical composition cally acceptable salt thereof. Preferably, mifepristone is to be comprising (a) pipamperon, and (b) a GPCR modulator, pref administered in a daily dose of between 600 and 1200 mg of erably R1204 or a pro-drug oran active metabolite thereof, or the active ingredient. a pharmaceutically acceptable salt thereof, as a combined The invention also relates to a pharmaceutical composition preparation for simultaneous, separate or sequential use for 25 comprising (a) pipamperon, and (b) a GRantagonist, prefer treating the underlying emotion dysregulation of a mental ably chosen from the group consisting of ORG 34517/34850 disease or disorder which is chosen from the group of diseases and mifepristone, preferably mifepristone, or a pro-drug oran or disorders consisting of mood disorders, anxiety disorders, active metabolite thereof, or a pharmaceutically acceptable eating disorders, premenstrual syndrome, Somatoform disor salt thereof, as a combined preparation for simultaneous, 30 separate or sequential use for treating the underlying emotion ders (excluding pain disorders), factitious disorders, disso dysregulation of a mental disease or disorder which is chosen ciative disorders, sexual and gender identity disorders, sleep from the group of diseases or disorders consisting of mood disorders, adjustment disorders, impulse control disorders, disorders, anxiety disorders, eating disorders, premenstrual Substance-related disorders, personality disorders, bereave syndrome, Somatoform disorders (excluding pain disorders), ment, occupational problem, problems related to abuse or 35 factitious disorders, dissociative disorders, sexual and gender neglect and pain disorders. identity disorders, sleep disorders, adjustment disorders, 41: Combination Therapy with an GR (Glucocorticoid impulse control disorders, Substance-related disorders, per Receptor) Antagonist Sonality disorders, bereavement, occupational problem, The mental disorders which can be treated using com problems related to abuse or neglect and pain disorders. pounds having a high selective affinity for the 5-HT2A and 40 The invention also relates to a pharmaceutical composition D4 receptor, for instance pipamperon, in a combination as described above wherein pipamperon is provided in a therapy with an GR (glucocorticoid receptor) antagonist, are unitary dose of between 5 and 15 mg of the active ingredient chosen from the group of diseases or disorders consisting of and wherein said GR antagonist is Mifepristone, preferably mood disorders, anxiety disorders, eating disorders, premen provided in a unitary dose of between 600 and 1200 mg of the strual syndrome, Somatoform disorders (excluding pain dis 45 active ingredient. orders), factitious disorders, dissociative disorders, sexual 42: Combination Therapy with a Histamine H3-Receptor and gender identity disorders, sleep disorders, adjustment Antagonist disorders, impulse control disorders, Substance-related disor The mental disorders which can be treated using com ders, personality disorders, bereavement, occupational prob pounds having a high selective affinity for the 5-HT2A and lem, problems related to abuse or neglect and pain disorders. 50 D4 receptor, for instance pipamperon, in a combination The present invention thus relates to the use of pipamperon therapy with a histamine H3-receptor antagonist, are chosen or a pharmaceutically acceptable salt thereof for the prepara from the group of diseases or disorders consisting of Alzhe tion of a medicament for treating the underlying emotion imer Disease, Substance-induced persisting dementia, Vascu dysregulation of a non-cognitive mental disease or disorder lar dementia, dementia due to HIV disease, dementia due to selected from the group of diseases and disorders consisting 55 head trauma, dementia due to Parkinson Disease, dementia of mood disorders, anxiety disorders, eating disorders, pre due to Huntington Disease, dementia due to Pick Disease, menstrual syndrome, Somatoform disorders (excluding pain dementia due to Creutzfeldt-Jacob Disease, amnestic disor disorders), factitious disorders, dissociative disorders, sexual ders due to a general medical condition, Substance-induced and gender identity disorders, sleep disorders, adjustment persisting amnestic disorder, mild cognitive impairment dis disorders, impulse control disorders, Substance-related disor 60 order and other cognitive disorders. ders, personality disorders, bereavement, occupational prob The present invention thus relates to the use of pipamperon lem and problems related to abuse or neglect, characterized in or a pharmaceutically acceptable salt thereof for the prepara that pipamperon or said pharmaceutically acceptable salt tion of a medicament for treating the underlying emotion thereof is administered simultaneously with, separate from or dysregulation of a cognitive mental disease or disorder prior to the administration of a GR antagonist compound to 65 selected from the group of diseases and disorders consisting augment the therapeutic effect or to provide a faster onset of of Alzheimer Disease, Substance-induced persisting demen the therapeutic effect of said GR antagonist compound, fur tia, Vascular dementia, dementia due to HIV disease, demen US 8,304,431 B2 57 58 tia due to head trauma, dementia due to Parkinson Disease, between 0.075 and 0.6 mg of the active ingredient. More dementia due to Huntington Disease, dementia due to Pick preferably, said hormonal Substance is a drosiperone/ethinyl Disease, dementia due to Creutzfeldt-Jacob Disease, amnes estradiol composition and is to be administered as a daily dose tic disorders due to a general medical condition, Substance in tablets, preferably comprising 3 mg drosiperone and 0.02 induced persisting amnestic disorder, mild cognitive impair mg ethinyl estradiol of the active ingredients, respectively. ment disorder and other cognitive disorders, characterized in The invention also relates to a pharmaceutical composition that pipamperon or said pharmaceutically acceptable salt comprising (a) pipamperon, and (b) a hormonal Substance, thereof is administered simultaneously with, separate from or preferably chosen from the group consisting of a testosterone prior to the administration of a histamine H3-receptorantago transdermal spray, a testosterone gel, a female testosterone nist compound to augment the therapeutic effect or to provide 10 patch, synthetic conjugated estrogen A, methyltestosterone, a a faster onset of the therapeutic effect of said histamine estrogens/methyltestosterone and a drosiperone/ethinyl H3-receptor antagonist compound, further characterized in estradiol composition, or a pro-drug or an active metabolite that pipamperon is to be administered to a patient in a daily thereof, or a pharmaceutically acceptable salt thereof, as a dose ranging between 5 and 15 mg of the active ingredient. combined preparation for simultaneous, separate or sequen According to a preferred embodiment, the invention relates 15 tial use for treating the underlying emotion dysregulation of a to the uses as described above, wherein said histamine H3-re cognitive mental disease or disorder which is chosen from the ceptor antagonist compound is chosen from the group of group consisting of premenstrual syndrome and sexual and compounds consisting of ABT-834 and ABT-239, or a pro gender identity disorders. drug or an active metabolite thereof, or a pharmaceutically The invention also relates to a pharmaceutical composition acceptable salt thereof. as described above wherein pipamperon is provided in a The invention also relates to a pharmaceutical composition unitary dose of between 5 and 15 mg of the active ingredient comprising (a) pipamperon, and (b) a histamine H3-receptor and wherein said hormonal Substance is synthetic conjugated antagonist, preferably chosen from the group consisting of estrogen A, preferably provided in a unitary dose of between ABT-834 and ABT-239 or a pro-drug or an active metabolite 0.075 and 0.6 mg of the active ingredient. thereof, or a pharmaceutically acceptable salt thereof, as a 25 The invention also relates to a pharmaceutical composition combined preparation for simultaneous, separate or sequen as described above wherein pipamperon is provided in a tial use for treating the underlying emotion dysregulation of a unitary dose of between 5 and 15 mg of the active ingredient cognitive mental disease or disorder which is chosen from the and wherein said hormonal Substance is a drosiperone/ethinyl group consisting of Alzheimer Disease, Substance-related estradiol composition, preferably provided in tablets com persisting dementia, Vascular dementia, dementia due to HIV 30 prising a unitary dose of 3 mg drosiperone and 0.02 mg disease, dementia due to head trauma, dementia due to Par ethinyl estradiol of the active ingredients, respectively. kinson Disease, dementia due to Huntington Disease, demen 44: Combination Therapy with a Compound which Increases tia due to Pick Disease, dementia due to Creutzfeldt-Jacob Brain Concentrations of 5-HT Disease, amnestic disorders due to a general medical condi The mental disorders which can be treated using com tion, Substance-induced persisting amnestic disorder, mild 35 pounds having a high selective affinity for the 5-HT2A and cognitive impairment disorder and other cognitive disorders. D4 receptor, for instance pipamperon, in a combination 43: Combination Therapy with a Hormonal Substance therapy with a compound which increases brain concentra The mental disorders which can be treated using com tions of 5-HT (serotonin), are chosen from the group of dis pounds having a high selective affinity for the 5-HT2A and eases or disorders consisting of mood disorders, anxiety dis D4 receptor, for instance pipamperon, in a combination 40 orders, eating disorders, premenstrual syndrome, therapy with a hormonal Substance, are chosen from the Somatoform disorders (excluding pain disorders), factitious group of diseases or disorders consisting of premenstrual disorders, dissociative disorders, sexual and gender identity syndrome and sexual and gender identity disorders. disorders, sleep disorders, adjustment disorders, impulse The present invention thus relates to the use of pipamperon control disorders, Substance-related disorders, personality or a pharmaceutically acceptable salt thereof for the prepara 45 disorders, bereavement, occupational problem, problems tion of a medicament for treating the underlying emotion related to abuse or neglect and pain disorders. dysregulation of a cognitive mental disease or disorder The present invention thus relates to the use of pipamperon selected from the group of diseases and disorders consisting or a pharmaceutically acceptable salt thereof for the prepara of premenstrual syndrome and sexual and gender identity tion of a medicament for treating the underlying emotion disorders, characterized in that pipamperon or said pharma 50 dysregulation of a non cognitive mental disease or disorder ceutically acceptable salt thereof is administered simulta selected from the group of diseases and disorders consisting neously with, separate from or prior to the administration of a of mood disorders, anxiety disorders, eating disorders, pre hormonal Substance to augment the therapeutic effect or to menstrual syndrome, Somatoform disorders (excluding pain provide a faster onset of the therapeutic effect of said hor disorders), factitious disorders, dissociative disorders, sexual monal Substance, further characterized in that pipamperon is 55 and gender identity disorders, sleep disorders, adjustment to be administered to a patient in a daily dose ranging between disorders, impulse control disorders, Substance-related disor 5 and 15 mg of the active ingredient. ders, personality disorders, bereavement, occupational prob According to a preferred embodiment, the invention relates lemand problems related to abuse or neglect, characterized in to the uses as described above, wherein said hormonal Sub that pipamperon or said pharmaceutically acceptable salt stance is chosen from the group consisting of a testosterone 60 thereof is administered simultaneously with, separate from or transdermal spray, a testosterone gel, a female testosterone prior to the administration of a compound which increases patch, synthetic conjugated estrogen A, methyltestosterone, a brain concentrations of 5-HT (serotonin) to augment the estrogens/methyltestosterone and a drosiperone/ethinyl therapeutic effect or to provide a faster onset of the therapeu estradiol composition, or a pro-drug or an active metabolite tic effect of said compound which increases brain concentra thereof, or a pharmaceutically acceptable salt thereof. More 65 tions of 5-HT (serotonin), further characterized in that pipam preferably, said hormonal Substance is synthetic conjugated peron is to be administered to a patient in a daily dose ranging estrogen A and is to be administered in a daily dose ranging between 5 and 15 mg of the active ingredient. US 8,304,431 B2 59 60 The present invention thus relates to the use of pipamperon insulin sensitivity to augment the therapeutic effect or to or a pharmaceutically acceptable salt thereof for the prepara provide a faster onset of the therapeutic effect of said com tion of a medicament for treating the underlying emotion pound which increases insulin sensitivity, further character dysregulation of pain, characterized in that pipamperon or ized in that pipamperon is to be administered to a patient in a said pharmaceutically acceptable salt thereof is administered 5 daily dose ranging between 5 and 15 mg of the active ingre simultaneously with, separate from or prior to the adminis dient. tration of a compound which increases brain concentrations According to a preferred embodiment, the invention relates of 5-HT (serotonin) to augment the therapeutic effect or to to the use as described above, wherein said compound which provide a faster onset of the therapeutic effect of said com increases insulin sensitivity is rosiglitaZone maleate, or a pound which increases brain concentrations of 5-HT (seroto 10 nin), further characterized in that pipamperon is to be admin pro-drug or an active metabolite thereof, or a pharmaceuti istered to a patient in a daily dose ranging between 5 and 15 cally acceptable salt thereof. mg of the active ingredient. The invention also relates to a pharmaceutical composition According to a preferred embodiment, the invention relates comprising (a) pipamperon, and (b) a compound which to the uses as described above, wherein said compound which 15 increases insulin sensitivity, preferably rosiglitaZone maleate increases brain concentrations of 5-HT (serotonin) is chosen or a pro-drug or an active metabolite thereof, or a pharma from the group consisting of triptosine, SP 186, PMD 145 and ceutically acceptable salt thereof, as a combined preparation KW 6055, or a pro-drug or an active metabolite thereof, or a for simultaneous, separate or sequential use for treating the pharmaceutically acceptable salt thereof. underlying emotion dysregulation of a cognitive mental dis The invention also relates to a pharmaceutical composition ease or disorder which is chosen from the group consisting of comprising (a) pipamperon, and (b) a compound which Alzheimer Disease, Substance-induced persisting dementia, increases brain concentrations of 5-HT (serotonin), prefer vascular dementia, dementia due to HIV disease, dementia ably chosen from the group consisting of triptosine, SP 186, due to head trauma, dementia due to Parkinson Disease, PMD 145 and KW 6055, or a pro-drug oran active metabolite dementia due to Huntington Disease, dementia due to Pick thereof, or a pharmaceutically acceptable salt thereof, as a 25 Disease, dementia due to Creutzfeldt-Jacob Disease, amnes combined preparation for simultaneous, separate or sequen tic disorders due to a general medical condition, Substance tial use for treating the underlying emotion dysregulation of a induced persisting amnestic disorder, mild cognitive impair mental disease or disorder which is chosen from the group of ment disorder and other cognitive disorders. diseases and disorders consisting of mood disorders, anxiety 46: Combination Therapy with a Compound Inhibiting the disorders, eating disorders, premenstrual syndrome, Somato 30 Mixed Lineage Kinase Family form disorders (excluding pain disorders), factitious disor The mental disorder which can be treated using com ders, dissociative disorders, sexual and gender identity disor pounds having a high selective affinity for the 5-HT2A and ders, sleep disorders, adjustment disorders, impulse control D4 receptor, for instance pipamperon, in a combination disorders, Substance-related disorders, personality disorders, therapy with a compound which is an inhibitor of the mixed bereavement, occupational problem, problems related to 35 lineage kinase family is Parkinson Disease. abuse or neglect and pain disorders. The present invention thus relates to the use of pipamperon 45: Combination Therapy with a Compound which Increases or a pharmaceutically acceptable salt thereof for the prepara Insulin Sensitivity tion of a medicament for treating the underlying emotion The mental disorders which can be treated using com dysregulation of Parkinson Disease, characterized in that pounds having a high selective affinity for the 5-HT2A and 40 pipamperon or said pharmaceutically acceptable salt thereof D4 receptor, for instance pipamperon, in a combination is administered simultaneously with, separate from or prior to therapy with a compound which increases insulin sensitivity, the administration of a compound which is an inhibitor of the are chosen from the group of diseases or disorders consisting mixed lineage kinase family to augment the therapeutic effect of Alzheimer Disease, Substance-induced persisting demen or to provide a faster onset of the therapeutic effect of said tia, Vascular dementia, dementia due to HIV disease, demen 45 compound which is an inhibitor of the mixed lineage kinase tia due to head trauma, dementia due to Parkinson Disease, family, further characterized in that pipamperon is to be dementia due to Huntington Disease, dementia due to Pick administered to a patient in a daily dose ranging between 5 Disease, dementia due to Creutzfeldt-Jacob Disease, amnes and 15 mg of the active ingredient. tic disorders due to a general medical condition, Substance According to a preferred embodiment, the invention relates induced persisting amnestic disorder, mild cognitive impair 50 to the use as described above, wherein said compound which ment disorder and other cognitive disorders. is an inhibitor of the mixed lineage kinase family is CEP-1347 The present invention thus relates to the use of pipamperon or a pro-drug or an active metabolite thereof, or a pharma or a pharmaceutically acceptable salt thereof for the prepara ceutically acceptable salt thereof. tion of a medicament for treating the underlying emotion The invention also relates to a pharmaceutical composition dysregulation of a cognitive mental disease or disorder 55 comprising (a) pipamperon, and (b) a compound which is an selected from the group of diseases and disorders consisting inhibitor of the mixed lineage kinase family, preferably CEP of Alzheimer Disease, Substance-induced persisting demen 1347 or a pro-drug or an active metabolite thereof, or a phar tia, Vascular dementia, dementia due to HIV disease, demen maceutically acceptable salt thereof, as a combined prepara tia due to head trauma, dementia due to Parkinson Disease, tion for simultaneous, separate or sequential use for treating dementia due to Huntington Disease, dementia due to Pick 60 the underlying emotion dysregulation of Parkinson Disease. Disease, dementia due to Creutzfeldt-Jacob Disease, amnes 47: Combination Therapy with an Interleukin-1 Beta Con tic disorders due to a general medical condition, Substance verting Enzyme Inhibitor Compound induced persisting amnestic disorder, mild cognitive impair The mental disorder which can be treated using com ment disorder and other cognitive disorders, characterized in pounds having a high selective affinity for the 5-HT2A and that pipamperon or said pharmaceutically acceptable salt 65 D4 receptor, for instance pipamperon, in a combination thereof is administered simultaneously with, separate from or therapy with an interleukin-1beta converting enzyme inhibi prior to the administration of a compound which increases tor compound, is a pain disorder. US 8,304,431 B2 61 62 The present invention thus relates to the use of pipamperon ranging between 1000 mg/50 mg, more preferably between or a pharmaceutically acceptable salt thereof for the prepara 500 mg/100 mg, and most preferably 200 mg of the active tion of a medicament for treating the underlying emotion ingredients per day. dysregulation of a pain disorder, characterized in that pipam The invention also relates to a pharmaceutical composition peron or said pharmaceutically acceptable salt thereof is comprising (a) pipamperon, and (b) a levodopa/decarboylase administered simultaneously with, separate from or prior to inhibitor compound, preferably levodopa/carbidopa, the administration of an interleukin-1beta converting enzyme levodopa/benserazide, etilevodopa/carbidopa or etilevodopa/ inhibitor compound to augment the therapeutic effect or to benserazide, or a pro-drug or an active metabolite thereof, or provide a faster onset of the therapeutic effect of said inter a pharmaceutically acceptable salt thereof, as a combined leukin-1beta converting enzyme inhibitor compound, further 10 preparation for simultaneous, separate or sequential use for characterized in that pipamperon is to be administered to a treating the underlying emotion dysregulation of Parkinson patient in a daily dose ranging between 5 and 15 mg of the Disease. The invention also relates to a pharmaceutical com active ingredient. position comprising (a) pipamperon, and (b) a levodopa/de According to a preferred embodiment, the invention relates carboylase inhibitor compound, preferably is (eti)levodopa/ to the use as described above, wherein said interleukin-1beta 15 carbidopa, or a pro-drug or an active metabolite thereof, or a converting enzyme inhibitor is prainacasan or a pro-drug or pharmaceutically acceptable salt thereof in combination with an active metabolite thereof, or a pharmaceutically accept entacapone, which is an inhibitor of catechol-O-methyltrans able salt thereof. ferase (COMT), or a pro-drug oran active metabolite thereof, The invention also relates to a pharmaceutical composition or a pharmaceutically acceptable salt thereof, as a combined comprising (a) pipamperon, and (b) an interleukin-1 beta preparation for simultaneous, separate or sequential use for converting enzyme inhibitor, preferably prainacasan or a pro treating the underlying emotion dysregulation of Parkinson drug or an active metabolite thereof, or a pharmaceutically Disease. acceptable salt thereof, as a combined preparation for simul The invention also relates to a pharmaceutical composition taneous, separate or sequential use for treating the underlying as described above wherein pipamperon is provided in a emotion dysregulation of a pain disorder, 25 unitary dose of between 5 and 15 mg of the active ingredient 48: Combination Therapy with a Levodopa/Decarboylase and wherein said levodopa/decarboylase inhibitor compound Inhibitor Compound is levodopa/carbidopa, preferably provided in a unitary dose The mental disorder which can be treated using com of between 250 to 600 mg and 25 to 150 mg of the active pounds having a high selective affinity for the 5-HT2A and ingredients. D4 receptor, for instance pipamperon, in a combination 30 The invention also relates to a pharmaceutical composition therapy with a levodopa? decarboylase inhibitor compound, is as described above wherein pipamperon is provided in a Parkinson Disease. unitary dose of between 5 and 15 mg of the active ingredient The present invention thus relates to the use of pipamperon and wherein said levodopa/decarboylase inhibitor compound or a pharmaceutically acceptable salt thereof for the prepara is levodopa/benserazide, preferably provided in a unitary tion of a medicament for treating the underlying emotion 35 dose of between 100 to 600 mg and 25 to 150 mg of the active dysregulation of Parkinson Disease, characterized in that ingredients. pipamperon or said pharmaceutically acceptable salt thereof The invention also relates to a pharmaceutical composition is administered simultaneously with, separate from or prior to as described above wherein pipamperon is provided in a the administration of a levodopa/decarboylase inhibitor com unitary dose of between 5 and 15 mg of the active ingredient pound to augment the therapeutic effect or to provide a faster 40 and wherein said levodopa/decarboylase inhibitor compound onset of the therapeutic effect of said levodopa/decarboylase is levodopa/carbidopa or etilevodopa/carbidopa in combina inhibitor compound, further characterized in that pipamperon tion with entacapone, of which the latter is preferably pro is to be administered to a patient in a daily dose ranging vided in a unitary dose of between 500 mg and 100 mg of the between 5 and 15 mg of the active ingredient. active ingredient. According to a preferred embodiment, the invention relates 45 49: Combination Therapy with a Lipid-DNA Complex to the use as described above, wherein said levodopa/decar The mental disorder which can be treated using com boylase inhibitor compound is chosen from the group con pounds having a high selective affinity for the 5-HT2A and sisting of levodopa/carbidopa, levodopa benserazide, eti D4 receptor, for instance pipamperon, in a combination levodopa/carbidopa or etilevodopa/benserazide, or a pro therapy with a lipid-DNA complex, is Parkinson Disease. drug or an active metabolite thereof, or a pharmaceutically 50 The present invention thus relates to the use of pipamperon acceptable salt thereof. Preferably, levodopa/carbidopa is to or a pharmaceutically acceptable salt thereof for the prepara be administered in a daily dose between 250 to 600 mg/25 to tion of a medicament for treating the underlying emotion 150 mg of the active ingredients. Preferably, levodopa/ dysregulation of Parkinson Disease, characterized in that benserazide is to be administered in a daily dose between 100 pipamperon or said pharmaceutically acceptable salt thereof to 600 mg/25 to 150 mg of the active ingredients. 55 is administered simultaneously with, separate from or prior to According to a further preferred embodiment, the inven the administration of lipid-DNA complex to augment the tion relates to the use as described above, wherein said therapeutic effect or to provide a faster onset of the therapeu levodopa/decarboylase inhibitor compound is (eti)levodopa/ tic effect of said lipid-DNA complex, further characterized in carbidopa, or a pro-drug or an active metabolite thereof, or a that pipamperon is to be administered to a patient in a daily pharmaceutically acceptable salt thereof in combination with 60 dose ranging between 5 and 15 mg of the active ingredient. entacapone, which is an inhibitor of catechol-O-methyltrans According to a preferred embodiment, the invention relates ferase (COMT), or a pro-drug oran active metabolite thereof, to the use as described above, wherein said lipid-DNA com or a pharmaceutically acceptable salt thereof. Preferably, said plex is GR213487B or a pro-drug or an active metabolite levodopa/decarboylase inhibitor compound is levodopa?car thereof, or a pharmaceutically acceptable salt thereof. bidopa and is to be administered in a dose ranging between 65 The invention also relates to a pharmaceutical composition 2000 mg/50 mg and 100 mg/10 mg of the active ingredients. comprising (a) pipamperon, and (b) a lipid-DNA complex, Preferably said entacapone is to be administered in a dose preferably GR213487B or a pro-drug or an active metabolite US 8,304,431 B2 63 64 thereof, or a pharmaceutically acceptable salt thereof, as a thereof is administered simultaneously with, separate from or combined preparation for simultaneous, separate or sequen prior to the administration of a monoamine oxidase A (MAO tial use for treating the underlying emotion dysregulation of A) and a monoamine oxidase B (MAO-B) reuptake inhibitor Parkinson Disease. compound to augment the therapeutic effect or to provide a 50: Combination Therapy with a Monoamine Oxidase faster onset of the therapeutic effect of said monoamine oxi (MAO) Reuptake Inhibitor dase A (MAO-A) and a monoamine oxidase B (MAO-B) The mental disorders which can be treated using com reuptake inhibitor compound, further characterized in that pounds having a high selective affinity for the 5-HT2A and pipamperon is to be administered to a patient in a daily dose D4 receptor, for instance pipamperon, in a combination ranging between 5 and 15 mg of the active ingredient. therapy with a monoamine oxidase (MAO) reuptake inhibi 10 tor, are chosen from the group of diseases or disorders con According to a preferred embodiment, the invention relates sisting of Substance related disorders and attention-deficit to the uses as described above, wherein said monoamine disorders (ADHD). oxidase A (MAO-A) and a monoamine oxidase B (MAO-B) The present invention thus relates to the use of pipamperon reuptake inhibitor compound is SPD473 or a pro-drug or an or a pharmaceutically acceptable salt thereof for the prepara 15 active metabolite thereof, or a pharmaceutically acceptable tion of a medicament for treating the underlying emotion salt thereof. dysregulation of non-cognitive mental disease or disorder The invention also relates to a pharmaceutical composition which are substance related disorders, characterized in that comprising (a) pipamperon, and (b) a monoamine oxidase A pipamperon or said pharmaceutically acceptable salt thereof (MAO-A) and a monoamine oxidase B (MAO-B) reuptake is administered simultaneously with, separate from or prior to inhibitor, preferably SPD473 or a pharmaceutically accept the administration of a monoamine oxidase (MAO) reuptake able salt thereof, as a combined preparation for simultaneous, inhibitor compound to augment the therapeutic effect or to separate or sequential use for treating the underlying emotion provide a faster onset of the therapeutic effect of said dysregulation of attention-deficit disorders. monoamine oxidase (MAO) reuptake inhibitor compound, 52: Combination Therapy with a Monoamine Oxidase B further characterized in that pipamperon is to be administered 25 (MAO-B) Inhibitor to a patientina daily dose ranging between 5 and 15 mg of the The mental disorders which can be treated using com active ingredient. pounds having a high selective affinity for the 5-HT2A and The present invention thus relates to the use of pipamperon D4 receptor, for instance pipamperon, in a combination or a pharmaceutically acceptable salt thereof for the prepara therapy with a monoamine oxidase B (MAO-B) inhibitor, are tion of a medicament for treating the underlying emotion 30 chosen from the group of diseases or disorders consisting of dysregulation of attention-deficit disorders (ADHD), charac mood disorders, anxiety disorders, eating disorders, premen terized in that pipamperon or said pharmaceutically accept strual syndrome, somatoform disorders (excluding pain dis able salt thereof is administered simultaneously with, sepa orders), factitious disorders, dissociative disorders, adjust rate from or prior to the administration of a monoamine ment disorders, impulse control disorders, attention-deficit oxidase (MAO) reuptake inhibitor compound to augment the 35 disorders, Substance-related disorders, personality disorders, therapeutic effect or to provide a faster onset of the therapeu problems related to abuse or neglect, pain disorder and Par tic effect of said monoamine oxidase (MAO) reuptake inhibi kinson Disease. tor compound, further characterized in that pipamperon is to The present invention thus relates to the use of pipamperon be administered to a patient in a daily dose ranging between 5 or a pharmaceutically acceptable salt thereof for the prepara and 15 mg of the active ingredient. 40 tion of a medicament for treating the underlying emotion According to a preferred embodiment, the invention relates dysregulation of a non-cognitive mental disease or disorder to the uses as described above, wherein said monoamine selected from the group of diseases and disorders consisting oxidase (MAO) reuptake inhibitor compound is NS 2359 or a of mood disorders, anxiety disorders, eating disorders, pre pro-drug or an active metabolite thereof, or a pharmaceuti menstrual syndrome, Somatoform disorders (excluding pain cally acceptable salt thereof. 45 disorders), factitious disorders, dissociative disorders, adjust The invention also relates to a pharmaceutical composition ment disorders, impulse control disorders, attention-deficit comprising (a) pipamperon, and (b) a monoamine oxidase disorders, Substance-related disorders, personality disorders, (MAO) reuptake inhibitor, preferably NS 2359 or a pro-drug problems related to abuse or neglect, characterized in that oran active metabolite thereof, or a pharmaceutically accept pipamperon or said pharmaceutically acceptable salt thereof able salt thereof, as a combined preparation for simultaneous, 50 is administered simultaneously with, separate from or prior to separate or sequential use for treating the underlying emotion the administration of a monoamine oxidase B (MAO-B) dysregulation of a mental disease or disorder which is chosen inhibitor compound to augment the therapeutic effect or to from the group consisting of Substance related disorders and provide a faster onset of the therapeutic effect of said attention-deficit disorders (ADHD). monoamine oxidase B (MAO-B) inhibitor compound, further 51: Combination Therapy with a MAO-A and a MAO-B 55 characterized in that pipamperon is to be administered to a Reuptake Inhibitor patient in a daily dose ranging between 5 and 15 mg of the The mental disorders which can be treated using com active ingredient. pounds having a high selective affinity for the 5-HT2A and The present invention thus relates to the use of pipamperon D4 receptor, for instance pipamperon, in a combination or a pharmaceutically acceptable salt thereof for the prepara therapy with a monoamine oxidase A (MAO-A) and a 60 tion of a medicament for treating the underlying emotion monoamine oxidase B (MAO-B) reuptake inhibitor, wherein dysregulation of pain disorders, characterized in that pipam said disorders are attention-deficit disorders. peron or said pharmaceutically acceptable salt thereof is The present invention thus relates to the use of pipamperon administered simultaneously with, separate from or prior to or a pharmaceutically acceptable salt thereof for the prepara the administration of a monoamine oxidase B (MAO-B) tion of a medicament for treating the underlying emotion 65 inhibitor compound to augment the therapeutic effect or to dysregulation of attention-deficit disorders, characterized in provide a faster onset of the therapeutic effect of said that pipamperon or said pharmaceutically acceptable salt monoamine oxidase B (MAO-B) inhibitor compound, further US 8,304,431 B2 65 66 characterized in that pipamperon is to be administered to a therapy with a monoamine oxidase B (MAO-B) reuptake patient in a daily dose ranging between 5 and 15 mg of the inhibitor, is Parkinson Disease. active ingredient. The present invention thus relates to the use of pipamperon The present invention thus relates to the use of pipamperon or a pharmaceutically acceptable salt thereof for the prepara or a pharmaceutically acceptable salt thereof for the prepara tion of a medicament for treating the underlying emotion tion of a medicament for treating the underlying emotion dysregulation of Parkinson Disease, characterized in that dysregulation of Parkinson Disease, characterized in that pipamperon or said pharmaceutically acceptable salt thereof pipamperon or said pharmaceutically acceptable salt thereof is administered simultaneously with, separate from or prior to is administered simultaneously with, separate from or prior to the administration of a monoamine oxidase B (MAO-B) the administration of a monoamine oxidase B (MAO-B) 10 reuptake inhibitor to augment the therapeutic effect or to inhibitor compound to augment the therapeutic effect or to provide a faster onset of the therapeutic effect of said provide a faster onset of the therapeutic effect of said monoamine oxidase B (MAO-B) reuptake inhibitor, further monoamine oxidase B (MAO-B) inhibitor compound, further characterized in that pipamperon is to be administered to a characterized in that pipamperon is to be administered to a patient in a daily dose ranging between 5 and 15 mg of the patient in a daily dose ranging between 5 and 15 mg of the 15 active ingredient. active ingredient. According to a preferred embodiment, the invention relates According to a preferred embodiment, the invention relates to the use as described above, wherein said monoamine oxi to the uses as described above, wherein said monoamine dase B (MAO-B) reuptake inhibitor is safinamide or a pro oxidase B (MAO-B) inhibitor compound is chosen from the drug or an active metabolite thereof, or a pharmaceutically group consisting of Selegiline, rasagiline (TVP-1012) and acceptable salt thereof. EmSam (transdermal selegiline), or a pro-drug or an active The invention also relates to a pharmaceutical composition metabolite thereof, or a pharmaceutically acceptable salt comprising (a) pipamperon, and (b) a monoamine oxidase B thereof. More preferably, said monoamine oxidase B (MAO (MAO-B) reuptake inhibitor, preferably safinamide or a pro B) inhibitor is selegiline and is to be administered in a daily drug or an active metabolite thereof, or a pharmaceutically dose ranging between 5 and 60 mg or possibly between 5 and 25 acceptable salt thereof, as a combined preparation for simul 10 mg of the active ingredient. In a further preferred embodi taneous, separate or sequential use for treating the underlying ment, selegiline is to be administered in a transdermal appli emotion dysregulation of Parkinson Disease. cation in a daily dose ranging between 5 and 60 mg of the 54: Combination Therapy with a Melanocortin-4 (MC4) active ingredient. In another preferred embodiment, sel Receptor Antagonist Compound egiline is to be administered orally in a daily dose ranging 30 The mental disorders which can be treated using com between 5 and 10 mg of the active ingredient. More prefer pounds having a high selective affinity for the 5-HT2A and ably, said monoamine oxidase B (MAO-B) inhibitor is rasa D4 receptor, for instance pipamperon, in a combination giline (TVP-1012) and is to be administered in a daily dose therapy with a melanocortin-4 (MC4) receptor antagonist ranging between 1 and 2 mg of the active ingredient. compound, are chosen from the group of diseases or disorders The invention also relates to a pharmaceutical composition 35 consisting of mood disorders, anxiety disorders, eating dis comprising (a) pipamperon, and (b) a monoamine oxidase B orders, premenstrual syndrome, Somatoform disorders (ex (MAO-B) inhibitor, preferably chosen from the group con cluding pain disorders), factitious disorders, dissociative dis sisting of selegiline, rasagiline (TVP-1012) and EmSam orders, sexual and gender identity disorders, sleep disorders, (transdermal selegiline), or a pro-drug oran active metabolite adjustment disorders, impulse control disorders, Substance thereof, or a pharmaceutically acceptable salt thereof, as a 40 related disorders, personality disorders, bereavement, occu combined preparation for simultaneous, separate or sequen pational problem, problems related to abuse or neglect and tial use for treating the underlying emotion dysregulation of a pain disorders. mental disease or disorder which is chosen from the group The present invention thus relates to the use of pipamperon consisting of mood disorders, anxiety disorders, eating dis or a pharmaceutically acceptable salt thereof for the prepara orders, premenstrual syndrome, Somatoform disorders (ex 45 tion of a medicament for treating the underlying emotion cluding pain disorders), factitious disorders, dissociative dis dysregulation of a non-cognitive mental disease or disorder orders, adjustment disorders, impulse control disorders, selected from the group of diseases and disorders consisting attention-deficit disorders, Substance-related disorders, per of mood disorders, anxiety disorders, eating disorders, pre Sonality disorders, problems related to abuse or neglect, pain menstrual syndrome, Somatoform disorders (excluding pain disorder and Parkinson Disease. 50 disorders), factitious disorders, dissociative disorders, sexual The invention also relates to a pharmaceutical composition and gender identity disorders, sleep disorders, adjustment as described above wherein pipamperon is provided in a disorders, impulse control disorders, Substance-related disor unitary dose of between 5 and 15 mg of the active ingredient ders, personality disorders, bereavement, occupational prob and wherein said monoamine oxidase B (MAO-B) inhibitoris lemand problems related to abuse or neglect, characterized in selegiline, preferably provided in a unitary dose of between 5 55 that pipamperon or said pharmaceutically acceptable salt and 10 mg or between 5 and 60 mg of the active ingredient. thereof is administered simultaneously with, separate from or The invention also relates to a pharmaceutical composition prior to the administration of a melanocortin-4 (MC4) recep as described above wherein pipamperon is provided in a tor antagonist compound to augment the therapeutic effect or unitary dose of between 5 and 15 mg of the active ingredient to provide a faster onset of the therapeutic effect of said and wherein said monoamine oxidase B (MAO-B) inhibitoris 60 melanocortin-4 (MC4) receptor antagonist compound, fur rasagiline (TVP-1012), preferably provided in a unitary dose ther characterized in that pipamperon is to be administered to of between 1 and 2 mg of the active ingredient. a patient in a daily dose ranging between 5 and 15 mg of the 53: Combination Therapy with a Monoamine Oxidase B active ingredient. (MAO-B) Reuptake Inhibitor The present invention thus relates to the use of pipamperon The mental disorder which can be treated using com 65 or a pharmaceutically acceptable salt thereof for the prepara pounds having a high selective affinity for the 5-HT2A and tion of a medicament for treating the underlying emotion D4 receptor, for instance pipamperon, in a combination dysregulation of pain disorders, characterized in that pipam US 8,304,431 B2 67 68 peron or said pharmaceutically acceptable salt thereof is tion of a medicament for treating the underlying emotion administered simultaneously with, separate from or prior to dysregulation of pain disorders, characterized in that pipam the administration of a melanocortin-4 (MC4) receptor peron or said pharmaceutically acceptable salt thereof is antagonist compound to augment the therapeutic effect or to administered simultaneously with, separate from or prior to provide a faster onset of the therapeutic effect of said mel the administration of a melanin concentrating hormone anocortin-4 (MC4) receptor antagonist compound, further (MCH) receptor antagonist compound to augment the thera characterized in that pipamperon is to be administered to a peutic effect or to provide a faster onset of the therapeutic patient in a daily dose ranging between 5 and 15 mg of the effect of said melanin concentrating hormone (MCH) recep active ingredient. torantagonist compound, further characterized in that pipam According to a preferred embodiment, the invention relates 10 peron is to be administered to a patient in a daily dose ranging to the uses as described above, wherein said melanocortin-4 between 5 and 15 mg of the active ingredient. (MC4) receptor antagonist compound is MCL0129, or a pro According to a preferred embodiment, the invention relates drug or an active metabolite thereof, or a pharmaceutically to the uses as described above, wherein said melanin concen acceptable salt thereof. trating hormone (MCH) receptor antagonist compound is The invention also relates to a pharmaceutical composition 15 SNAP-7941 or a pro-drug or an active metabolite thereof, or comprising (a) pipamperon, and (b) a melanocortin-4 (MC4) a pharmaceutically acceptable salt thereof. receptor antagonist compound, preferably MCL0129 or a The invention also relates to a pharmaceutical composition pro-drug or an active metabolite thereof, or a pharmaceuti comprising (a) pipamperon, and (b) a melanin concentrating cally acceptable salt thereof, as a combined preparation for hormone (MCH) receptor antagonist compound, preferably simultaneous, separate or sequential use for treating the SNAP-7941 or a pro-drug or an active metabolite thereof, or underlying emotion dysregulation of a mental disease or dis a pharmaceutically acceptable salt thereof, as a combined order which is chosen from the group consisting of mood preparation for simultaneous, separate or sequential use for disorders, anxiety disorders, eating disorders, premenstrual treating the underlying emotion dysregulation of a mental syndrome, Somatoform disorders (excluding pain disorders), disease or disorder which is chosen from the group consisting factitious disorders, dissociative disorders, sexual and gender 25 of mood disorders, anxiety disorders, eating disorders, pre identity disorders, sleep disorders, adjustment disorders, menstrual syndrome, Somatoform disorders (excluding pain impulse control disorders, Substance-related disorders, per disorders), factitious disorders, dissociative disorders, sexual Sonality disorders, bereavement, occupational problem, and gender identity disorders, sleep disorders, adjustment problems related to abuse or neglect and pain disorders. disorders, impulse control disorders, Substance-related disor 55: Combination Therapy with a MCH Receptor Antagonist 30 ders, personality disorders, bereavement, occupational prob Compound lem, problems related to abuse or neglect and pain disorders. The mental disorders which can be treated using com 56: Combination Therapy with a Melatonin Receptor (MT) pounds having a high selective affinity for the 5-HT2A and Agonist Compound D4 receptor, for instance pipamperon, in a combination The mental disorders which can be treated using com therapy with a melanin concentrating hormone (MCH) recep 35 pounds having a high selective affinity for the 5-HT2A and tor antagonist compound, are chosen from the group of dis D4 receptor, for instance pipamperon, in a combination eases or disorders consisting of mood disorders, anxiety dis therapy with a melatonin receptor (MT) agonist compound, orders, eating disorders, premenstrual syndrome, are chosen from the group of diseases or disorders consisting Somatoform disorders (excluding pain disorders), factitious of mood disorders, anxiety disorders, eating disorders, pre disorders, dissociative disorders, sexual and gender identity 40 menstrual syndrome, Somatoform disorders (excluding pain disorders, sleep disorders, adjustment disorders, impulse disorders), factitious disorders, dissociative disorders, sexual control disorders, Substance-related disorders, personality and gender identity disorders, sleep disorders, adjustment disorders, bereavement, occupational problem, problems disorders, impulse control disorders, Substance-related disor related to abuse or neglect and pain disorders. ders, personality disorders, bereavement, occupational prob The present invention thus relates to the use of pipamperon 45 lem, problems related to abuse or neglect and pain disorders. or a pharmaceutically acceptable salt thereof for the prepara The present invention thus relates to the use of pipamperon tion of a medicament for treating the underlying emotion or a pharmaceutically acceptable salt thereof for the prepara dysregulation of a non-cognitive mental disease or disorder tion of a medicament for treating the underlying emotion selected from the group of diseases and disorders consisting dysregulation of a non-cognitive mental disease or disorder of mood disorders, anxiety disorders, eating disorders, pre 50 selected from the group of diseases and disorders consisting menstrual syndrome, Somatoform disorders (excluding pain of mood disorders, anxiety disorders, eating disorders, pre disorders), factitious disorders, dissociative disorders, sexual menstrual syndrome, Somatoform disorders (excluding pain and gender identity disorders, sleep disorders, adjustment disorders), factitious disorders, dissociative disorders, sexual disorders, impulse control disorders, Substance-related disor and gender identity disorders, sleep disorders, adjustment ders, personality disorders, bereavement, occupational prob 55 disorders, impulse control disorders, Substance-related disor lem and problems related to abuse or neglect, characterized in ders, personality disorders, bereavement, occupational prob that pipamperon or said pharmaceutically acceptable salt lemand problems related to abuse or neglect, characterized in thereof is administered simultaneously with, separate from or that pipamperon or said pharmaceutically acceptable salt prior to the administration of a melanin concentrating hor thereof is administered simultaneously with, separate from or mone (MCH) receptor antagonist compound to augment the 60 prior to the administration of a melatonin receptor (MT) therapeutic effect or to provide a faster onset of the therapeu agonist compound to augment the therapeutic effect or to tic effect of said melanin concentrating hormone (MCH) provide a faster onset of the therapeutic effect of said mela receptor antagonist compound, further characterized in that tonin receptor (MT) agonist compound, further characterized pipamperon is to be administered to a patient in a daily dose in that pipamperon is to be administered to a patient in a daily ranging between 5 and 15 mg of the active ingredient. 65 dose ranging between 5 and 15 mg of the active ingredient. The present invention thus relates to the use of pipamperon The present invention thus relates to the use of pipamperon or a pharmaceutically acceptable salt thereof for the prepara or a pharmaceutically acceptable salt thereof for the prepara US 8,304,431 B2 69 70 tion of a medicament for treating the underlying emotion the therapeutic effect or to provide a faster onset of the thera dysregulation of pain disorders, characterized in that pipam peutic effect of said metabotropic glutamate receptor peron or said pharmaceutically acceptable salt thereof is (MgluR) agonist compound, further characterized in that administered simultaneously with, separate from or prior to pipamperon is to be administered to a patient in a daily dose the administration of a melatonin receptor (MT) agonist com ranging between 5 and 15 mg of the active ingredient. pound to augment the therapeutic effect or to provide a faster The present invention thus relates to the use of pipamperon onset of the therapeutic effect of said melatonin receptor or a pharmaceutically acceptable salt thereof for the prepara (MT) agonist compound, further characterized in that pipam tion of a medicament for treating the underlying emotion peron is to be administered to a patient in a daily dose ranging dysregulation of pain disorders, characterized in that pipam between 5 and 15 mg of the active ingredient. 10 peron or said pharmaceutically acceptable salt thereof is According to a preferred embodiment, the invention relates administered simultaneously with, separate from or prior to to the uses as described above, wherein said melatonin recep the administration of a metabotropic glutamate receptor tor (MT) agonist compound is chosen from the group con (MgluR) agonist compound to augment the therapeutic effect sisting of ramelteon and agomelatine, or a pro-drug or an or to provide a faster onset of the therapeutic effect of said active metabolite thereof, or a pharmaceutically acceptable 15 metabotropic glutamate receptor (MgluR) agonist com salt thereof. More preferably, said melatonin receptor (MT) pound, further characterized in that pipamperon is to be agonist compound is agomelatine and is to be administered in administered to a patient in a daily dose ranging between 5 a daily dose ranging between 25 and 50 mg of the active and 15 mg of the active ingredient. ingredient. According to a preferred embodiment, the invention relates The invention also relates to a pharmaceutical composition to the uses as described above, wherein said metabotropic comprising (a) pipamperon, and (b) a melatonin receptor glutamate receptor (MgluR) agonist compound is PRE703 or (MT) agonist compound, preferably ramelteon or ago a pro-drug or an active metabolite thereof, or a pharmaceuti melatine or a pro-drug or an active metabolite thereof, or a cally acceptable salt thereof. pharmaceutically acceptable salt thereof, as a combined The invention also relates to a pharmaceutical composition preparation for simultaneous, separate or sequential use for 25 comprising (a) pipamperon, and (b) a metabotropic glutamate treating the underlying emotion dysregulation of a mental receptor (MgluR) agonist, preferably PRE703 or a pro-drug disease or disorder which is chosen from the group consisting oran active metabolite thereof, or a pharmaceutically accept of mood disorders, anxiety disorders, eating disorders, pre able salt thereof, as a combined preparation for simultaneous, menstrual syndrome, Somatoform disorders (excluding pain separate or sequential use for treating the underlying emotion disorders), factitious disorders, dissociative disorders, sexual 30 dysregulation of a mental disease or disorder which is chosen and gender identity disorders, sleep disorders, adjustment from the group consisting of anxiety disorders, somatoform disorders, impulse control disorders, substance-related disor disorders (excluding pain disorders), factitious disorders, dis ders, personality disorders, bereavement, occupational prob Sociative disorders, adjustment disorders, impulse control lem, problems related to abuse or neglect and pain disorders. disorders, Substance-related disorders, personality disorders, The invention also relates to a pharmaceutical composition 35 bereavement, occupational problem, problems related to as described above wherein pipamperon is provided in a abuse or neglect and pain disorders. unitary dose of between 5 and 15 mg of the active ingredient 58: Combination Therapy with a Compound Mimicking the and wherein said melatonin receptor (MT) agonist compound Effect of Nerve Growth Factor (NGF) is agomelatine, preferably provided in a unitary dose of The mental disorders which can be treated using com between 25 and 50 mg of the active ingredient. 40 pounds having a high selective affinity for the 5-HT2A and 57: Combination Therapy with a Metabotropic Glutamate D4 receptor, for instance pipamperon, in a combination Receptor (MgluR) Agonist Compound therapy with a compound which mimics the effect of nerve The mental disorders which can be treated using com growth factor (NGF), are chosen from the group of diseases or pounds having a high selective affinity for the 5-HT2A and disorders consisting of Alzheimer Disease, Substance-in D4 receptor, for instance pipamperon, in a combination 45 duced persisting dementia, Vascular dementia, dementia due therapy with a metabotropic glutamate receptor (MgluR) to HIV disease, dementia due to head trauma, dementia due to agonist compound, are chosen from the group of diseases or Parkinson Disease, dementia due to Huntington Disease, disorders consisting of anxiety disorders, Somatoform disor dementia due to Pick Disease, dementia due to Creutzfeldt ders (excluding pain disorders), factitious disorders, disso Jacob Disease, amnestic disorders due to a general medical ciative disorders, adjustment disorders, impulse control dis 50 condition, Substance-induced persisting amnestic disorder, orders, Substance-related disorders, personality disorders, mild cognitive impairment disorder, other cognitive disorders bereavement, occupational problem, problems related to and Parkinson Disease. abuse or neglect and pain disorders. The present invention thus relates to the use of pipamperon The present invention thus relates to the use of pipamperon or a pharmaceutically acceptable salt thereof for the prepara or a pharmaceutically acceptable salt thereof for the prepara 55 tion of a medicament for treating the underlying emotion tion of a medicament for treating the underlying emotion dysregulation of a cognitive mental disease or disorder dysregulation of a non-cognitive mental disease or disorder selected from the group of diseases and disorders consisting selected from the group of diseases and disorders consisting of Alzheimer Disease, Substance-induced persisting demen of anxiety disorders, somatoform disorders (excluding pain tia, Vascular dementia, dementia due to HIV disease, demen disorders), factitious disorders, dissociative disorders, adjust 60 tia due to head trauma, dementia due to Parkinson Disease, ment disorders, impulse control disorders, Substance-related dementia due to Huntington Disease, dementia due to Pick disorders, personality disorders, bereavement, occupational Disease, dementia due to Creutzfeldt-Jacob Disease, amnes problem and problems related to abuse or neglect, character tic disorders due to a general medical condition, Substance ized in that pipamperon or said pharmaceutically acceptable induced persisting amnestic disorder, mild cognitive impair salt thereof is administered simultaneously with, separate 65 ment disorder and other cognitive disorders, characterized in from or prior to the administration of a metabotropic that pipamperon or said pharmaceutically acceptable salt glutamate receptor (MgluR) agonist compound to augment thereof is administered simultaneously with, separate from or US 8,304,431 B2 71 72 prior to the administration of a compound which mimics the The present invention thus relates to the use of pipamperon effect of nerve growth factor (NGF) to augment the therapeu or a pharmaceutically acceptable salt thereof for the prepara tic effect or to provide a faster onset of the therapeutic effect tion of a medicament for treating the underlying emotion of said compound which mimics the effect of nerve growth dysregulation of a cognitive mental disease or disorder factor (NGF), further characterized in that pipamperon is to 5 selected from the group of diseases and disorders consisting be administered to a patient in a daily dose ranging between 5 of Alzheimer Disease, Substance-induced persisting demen and 15 mg of the active ingredient. tia, Vascular dementia, dementia due to HIV disease, demen The present invention thus relates to the use of pipamperon tia due to head trauma, dementia due to Parkinson Disease, or a pharmaceutically acceptable salt thereof for the prepara dementia due to Huntington Disease, dementia due to Pick 10 Disease, dementia due to Creutzfeldt-Jacob Disease, amnes tion of a medicament for treating the underlying emotion tic disorders due to a general medical condition, Substance dysregulation of Parkinson Disease, characterized in that induced persisting amnestic disorder, mild cognitive impair pipamperon or said pharmaceutically acceptable salt thereof ment disorder and other cognitive disorders, characterized in is administered simultaneously with, separate from or prior to that pipamperon or said pharmaceutically acceptable salt the administration of a compound which mimics the effect of 15 thereof is administered simultaneously with, separate from or nerve growth factor (NGF) to augment the therapeutic effect prior to the administration of a muscarinic receptor partial or to provide a faster onset of the therapeutic effect of said agonist compound to augment the therapeutic effect or to compound which mimics the effect of nerve growth factor provide a faster onset of the therapeutic effect of said musca (NGF), further characterized in that pipamperon is to be rinic receptor partial agonist compound, further characterized administered to a patient in a daily dose ranging between 5 in that pipamperon is to be administered to a patient in a daily and 15 mg of the active ingredient. dose ranging between 5 and 15 mg of the active ingredient. According to a preferred embodiment, the invention relates According to a preferred embodiment, the invention relates to the uses as described above, wherein said compound which to the use as described above, wherein said muscarinic recep mimics the effect of nerve growth factor (NGF) is xaliproden torpartial agonist compound is Sevimeline or a pro-drug oran or a pro-drug or an active metabolite thereof, or a pharma 25 active metabolite thereof, or a pharmaceutically acceptable ceutically acceptable salt thereof. More preferably, said com salt thereof. pound which mimics the effect of nerve growth factor (NGF) The invention also relates to a pharmaceutical composition is Xaliproden and is to be administered in a daily dose ranging comprising (a) pipamperon, and (b) a muscarinic receptor between 1 and 2 mg of the active ingredient. partial agonist compound, preferably Sevimeline or a pro The invention also relates to a pharmaceutical composition 30 drug or an active metabolite thereof, or a pharmaceutically comprising (a) pipamperon, and (b) a compound which mim acceptable salt thereof, as a combined preparation for simul ics the effect of nerve growth factor (NGF), preferably Xalip taneous, separate or sequential use for treating the underlying roden or a pro-drug or an active metabolite thereof, or a emotion dysregulation of a mental disease or disorder which pharmaceutically acceptable salt thereof, as a combined is chosen from the group consisting of Alzheimer Disease, preparation for simultaneous, separate or sequential use for 35 Substance-induced persisting dementia, Vascular dementia, treating the underlying emotion dysregulation of a mental dementia due to HIV disease, dementia due to head trauma, disease or disorder which is chosen from the group consisting dementia due to Parkinson Disease, dementia due to Hunting of Alzheimer Disease, Substance-induced persisting demen ton Disease, dementia due to Pick Disease, dementia due to tia, Vascular dementia, dementia due to HIV disease, demen Creutzfeldt-Jacob Disease, amnestic disorders due to a gen tia due to head trauma, dementia due to Parkinson Disease, 40 era medical condition, Substance-induced persisting amnestic dementia due to Huntington Disease, dementia due to Pick disorder, mild cognitive impairment disorder and other cog Disease, dementia due to Creutzfeldt-Jacob Disease, amnes nitive disorders. tic disorders due to a general medical condition, Substance 60: Combination Therapy with a Selective Nor-Adrenaline induced persisting amnestic disorder, mild cognitive impair Re-Uptake Inhibitor (NARI) Compound ment disorder, other cognitive disorders and Parkinson 45 The mental disorders which can be treated using com Disease. pounds having a high selective affinity for the 5-HT2A and The invention also relates to a pharmaceutical composition D4 receptor, for instance pipamperon, in a combination as described above wherein pipamperon is provided in a therapy with a selective nor-adrenaline re-uptake inhibitor unitary dose of between 5 and 15 mg of the active ingredient (NARI) compound, are chosen from the group of diseases or and wherein said compound which mimics the effect of nerve 50 disorders consisting of mood disorders, anxiety disorders, growth factor (NGF) is xaliproden, preferably provided in a adjustment disorders, attention-deficit disorders, personality unitary dose of between 1 and 2 mg of the active ingredient. disorders, antisocial behaviour, bereavement, occupational 59: Combination Therapy with a Muscarinic Receptor Partial problem, problems related to abuse or neglect and pain dis Agonist Compound orders. The mental disorders which can be treated using com 55 The present invention thus relates to the use of pipamperon pounds having a high selective affinity for the 5-HT2A and or a pharmaceutically acceptable salt thereof for the prepara D4 receptor, for instance pipamperon, in a combination tion of a medicament for treating the underlying emotion therapy with a muscarinic receptor partial agonist compound, dysregulation of a non-cognitive mental disease or disorder are chosen from the group of diseases or disorders consisting selected from the group of diseases and disorders consisting of Alzheimer Disease, Substance-induced persisting demen 60 of mood disorders, anxiety disorders, adjustment disorders, tia, Vascular dementia, dementia due to HIV disease, demen attention-deficit disorders, personality disorders, antisocial tia due to head trauma, dementia due to Parkinson Disease, behaviour, bereavement, occupational problem and problems dementia due to Huntington Disease, dementia due to Pick related to abuse or neglect, characterized in that pipamperon Disease, dementia due to Creutzfeldt-Jacob Disease, amnes or said pharmaceutically acceptable salt thereof is adminis tic disorders due to a general medical condition, Substance 65 tered simultaneously with, separate from or prior to the induced persisting amnestic disorder, mild cognitive impair administration of a selective nor-adrenaline re-uptake inhibi ment disorder and other cognitive disorders. tor (NARI) compound to augment the therapeutic effect or to US 8,304,431 B2 73 74 provide a faster onset of the therapeutic effect of said selective ders, dissociative disorders, sexual and gender identity disor nor-adrenaline re-uptake inhibitor (NARI) compound, fur ders, sleep disorders, adjustment disorders, impulse control ther characterized in that pipamperon is to be administered to disorders, personality disorders, antisocial behaviour, a patient in a daily dose ranging between 5 and 15 mg of the bereavement, occupational problem, problems related to active ingredient. abuse or neglect and pain disorders. The present invention thus relates to the use of pipamperon The present invention thus relates to the use of pipamperon or a pharmaceutically acceptable salt thereof for the prepara or a pharmaceutically acceptable salt thereof for the prepara tion of a medicament for treating the underlying emotion tion of a medicament for treating the underlying emotion dysregulation of pain disorders, characterized in that pipam dysregulation of a non-cognitive mental disease or disorder peron or said pharmaceutically acceptable salt thereof is 10 selected from the group of diseases and disorders consisting administered simultaneously with, separate from or prior to of mood disorders, anxiety disorders, eating disorders, pre the administration of a selective nor-adrenaline re-uptake menstrual syndrome, Somatoform disorders (excluding pain inhibitor (NARI) compound to augment the therapeutic effect disorders), factitious disorders, dissociative disorders, sexual or to provide a faster onset of the therapeutic effect of said and gender identity disorders, sleep disorders, adjustment selective nor-adrenaline re-uptake inhibitor (NARI) com 15 disorders, impulse control disorders, personality disorders, pound, further characterized in that pipamperon is to be antisocial behaviour, bereavement, occupational problemand administered to a patient in a daily dose ranging between 5 problems related to abuse or neglect, characterized in that and 15 mg of the active ingredient. pipamperon or said pharmaceutically acceptable salt thereof According to a preferred embodiment, the invention relates is administered simultaneously with, separate from or prior to to the uses as described above, wherein said selective nor the administration of a noradrenergic/specific serotonergic adrenaline re-uptake inhibitor (NARI) compound is chosen antidepressant (NaSSA) compound to augment the therapeu from the group consisting of reboxetine, atomoxetine hydro tic effect or to provide a faster onset of the therapeutic effect chloride, A75200, 155U88, (S)-A75200, or a pro-drug oran of said noradrenergic/specific serotonergic antidepressant active metabolite thereof, or a pharmaceutically acceptable (NaSSA) compound, further characterized in that pipam salt thereof. More preferably, said selective nor-adrenaline 25 peron is to be administered to a patient in a daily dose ranging re-uptake inhibitor (NARI) compound is reboxetine and is to between 5 and 15 mg of the active ingredient. be administered in a daily dose ranging between 8 and 12 mg The present invention thus relates to the use of pipamperon of the active ingredient. More preferably, said selective nor or a pharmaceutically acceptable salt thereof for the prepara adrenaline re-uptake inhibitor (NARI) compound is atomox tion of a medicament for treating the underlying emotion etine hydrochloride and is to be administered in a daily dose 30 dysregulation of pain disorders, characterized in that pipam ranging between 40 and 100 mg of the active ingredient. peron or said pharmaceutically acceptable salt thereof is The invention also relates to a pharmaceutical composition administered simultaneous y with, separate from or prior to comprising (a) pipamperon, and (b) a selective nor-adrena the administration of a noradrenergic/specific serotonergic line re-uptake inhibitor (NARI) compound, preferably cho antidepressant (NaSSA) compound to augment the therapeu Sen from the group consisting of reboxetine, atomoxetine 35 tic effect or to provide a faster onset of the therapeutic effect hydrochloride. A 75200, 155U88, (S)-A75200, or a pro-drug of said noradrenergic/specific serotonergic antidepressant oran active metabolite thereof, or a pharmaceutically accept (NaSSA) compound, further characterized in that pipam able salt thereof, as a combined preparation for simultaneous, peron is to be administered to a patient in a daily dose ranging separate or sequential use for treating the underlying emotion between 5 and 15 mg of the active ingredient. dysregulation of mental disease or disorder which is chosen 40 According to a preferred embodiment, the invention relates from the group consisting of mood disorders, anxiety disor to the uses as described above, wherein said noradrenergic/ ders, adjustment disorders, attention-deficit disorders, per specific serotonergic antidepressant (NaSSA) compound is Sonality disorders, antisocial behaviour, bereavement, occu ORG 4420 or a pro-drug or an active metabolite thereof, or a pational problem, problems related to abuse or neglect and pharmaceutically acceptable salt thereof. pain disorders. 45 The invention also relates to a pharmaceutical composition The invention also relates to a pharmaceutical composition comprising (a) pipamperon, and (b) a noradrenergic/specific as described above wherein pipamperon is provided in a serotonergic antidepressant (NaSSA) compound, preferably unitary dose of between 5 and 15 mg of the active ingredient ORG 4420 or a pro-drug or an active metabolite thereof, or a and wherein said selective nor-adrenaline re-uptake inhibitor pharmaceutically acceptable salt thereof, as a combined (NARI) compound is reboxetine, preferably provided in a 50 preparation for simultaneous, separate or sequential use for unitary dose of between 8 and 12 mg of the active ingredient. treating the underlying emotion dysregulation of mental dis The invention also relates to a pharmaceutical composition ease or disorder which is chosen from the group consisting of as described above wherein pipamperon is provided in a mood disorders, anxiety disorders, eating disorders, premen unitary dose of between 5 and 15 mg of the active ingredient strual syndrome, Somatoform disorders (excluding pain dis and wherein said selective nor-adrenaline re-uptake inhibitor 55 orders), factitious disorders, dissociative disorders, sexual (NARI) compound is atomoxetine hydrochloride, preferably and gender identity disorders, sleep disorders, adjustment provided in a unitary dose of between 40 and 100 mg of the disorders, impulse control disorders, personality disorders, active ingredient. antisocial behaviour, bereavement, occupational problem, 61. Combination Therapy with a NaSSA Compound problems related to abuse or neglect and pain disorders. The mental disorders which can be treated using com 60 62: Combination Therapy with a Selective NDRI Compound pounds having a high selective affinity for the 5-HT2A and The mental disorders which can be treated using com D4 receptor, for instance pipamperon, in a combination pounds having a high selective affinity for the 5-HT2A and therapy with a noradrenergic/specific serotonergic antide D4 receptor, for instance pipamperon, in a combination pressant (NaSSA) compound, are chosen from the group of therapy with a selective nor-adrenaline and dopamine re diseases or disorders consisting of mood disorders, anxiety 65 uptake inhibitor (NDRI) compound, are chosen from the disorders, eating disorders, premenstrual syndrome, Somato group of diseases or disorders consisting of mood disorders, form disorders (excluding pain disorders), factitious disor anxiety disorders, adjustment disorders, attention-deficit dis US 8,304,431 B2 75 76 orders, personality disorders, antisocial behaviour, bereave adrenaline and dopamine re-uptake inhibitor (NDRI) com ment, occupational problem, problems related to abuse or pound is GW353162 or a pro-drug or an active metabolite neglect, pain disorders, delirium, Alzheimer Disease, Sub thereof, or a pharmaceutically acceptable salt thereof. More stance-induced persisting dementia, vascular dementia, preferably, said selective nor-adrenaline and dopamine re dementia due to HIV disease, dementia due to head trauma, uptake inhibitor (NDRI) compound is GW353162 and is to be dementia due to Parkinson Disease, dementia due to Hunting administered in a daily dose ranging between 20 and 60 mg of ton Disease, dementia due to Pick Disease, dementia due to the active ingredient. Creutzfeldt-Jacob Disease, amnestic disorders due to a gen The invention also relates to a pharmaceutical composition eral medical condition, Substance-induced persisting amnes comprising (a) pipamperon, and (b) a selective nor-adrena tic disorder, mild cognitive impairment disorder and other 10 cognitive disorders. line and dopamine re-uptake inhibitor (NDRI) compound, The present invention thus relates to the use of pipamperon preferably GW353162 or a pro-drug or an active metabolite or a pharmaceutically acceptable salt thereof for the prepara thereof, or a pharmaceutically acceptable salt thereof, as a tion of a medicament for treating the underlying emotion combined preparation for simultaneous, separate or sequen dysregulation of a non-cognitive mental disease or disorder 15 tial use for treating the underlying emotion dysregulation of selected from the group of diseases and disorders consisting mental disease or disorder which is chosen from the group of mood disorders, anxiety disorders, adjustment disorders, consisting of mood disorders, anxiety disorders, adjustment attention-deficit disorders, personality disorders, antisocial disorders, attention-deficit disorders, personality disorders, behaviour, bereavement, occupational problem and problems antisocial behaviour, bereavement, occupational problem, related to abuse or neglect, characterized in that pipamperon problems related to abuse or neglect, pain disorders, delirium, or said pharmaceutically acceptable salt thereof is adminis Alzheimer Disease, Substance-induced persisting dementia, tered simultaneously with, separate from or prior to the vascular dementia, dementia due to HIV disease, dementia administration of a selective nor-adrenaline and dopamine due to head trauma, dementia due to Parkinson Disease, re-uptake inhibitor (NDRI) compound to augment the thera dementia due to Huntington Disease, dementia due to Pick peutic effect or to provide a faster onset of the therapeutic 25 Disease, dementia due to Creutzfeldt-Jacob Disease, amnes effect of said selective nor-adrenaline and dopamine re-up tic disorders due to a general medical condition, Substance take inhibitor (NDRI) compound, further characterized in induced persisting amnestic disorder, mild cognitive impair that pipamperon is to be administered to a patient in a daily ment disorder and other cognitive disorders. dose ranging between 5 and 15 mg of the active ingredient. The invention also relates to a pharmaceutical composition The present invention thus relates to the use of pipamperon 30 as described above wherein pipamperon is provided in a or a pharmaceutically acceptable salt thereof for the prepara unitary dose of between 5 and 15 mg of the active ingredient tion of a medicament for treating the underlying emotion and wherein said selective nor-adrenaline and dopamine re dysregulation of pain disorders, characterized in that pipam uptake inhibitor (NDRI) compound is GW353162, prefer peron or said pharmaceutically acceptable salt thereof is ably provided in a unitary dose of between 20 and 60 mg of administered simultaneously with, separate from or prior to 35 the active ingredient. the administration of a selective nor-adrenaline and dopamine 63: Combination Therapy with a Compound which is a Neu re-uptake inhibitor (NDRI) compound to augment the thera roimmunophilin Ligand peutic effect or to provide a faster onset of the therapeutic The mental disorder which can be treated using com effect of said selective nor-adrenaline and dopamine re-up pounds having a high selective affinity for the 5-HT2A and take inhibitor (NDRI) compound, further characterized in 40 D4 receptor, for instance pipamperon, in a combination that pipamperon is to be administered to a patient in a daily therapy with a compound which is a neuroimmunophilin dose ranging between 5 and 15 mg of the active ingredient. ligand, is Parkinson Disease. The present invention thus relates to the use of pipamperon The present invention thus relates to the use of pipamperon or a pharmaceutically acceptable salt thereof for the prepara or a pharmaceutically acceptable salt thereof for the prepara tion of a medicament for treating the underlying emotion 45 tion of a medicament for treating the underlying emotion dysregulation of a cognitive mental disease or disorder dysregulation of Parkinson Disease, characterized in that selected from the group of diseases and disorders consisting pipamperon or said pharmaceutically acceptable salt thereof of delirium, Alzheimer Disease, Substance-induced persist is administered simultaneously with, separate from or prior to ing dementia, Vascular dementia, dementia due to HIV dis the administration of a compound which is a neuroimmuno ease, dementia due to head trauma, dementia due to Parkinson 50 philin ligand to augment the therapeutic effect or to provide a Disease, dementia due to Huntington Disease, dementia due faster onset of the therapeutic effect of said compound which to Pick Disease, dementia due to Creutzfeldt-Jacob Disease, is a neuroimmunophilin ligand, further characterized in that amnestic disorders due to a general medical condition, Sub pipamperon is to be administered to a patient in a daily dose stance-induced persisting amnestic disorder, mild cognitive ranging between 5 and 15 mg of the active ingredient. impairment disorder and other cognitive disorders, character 55 According to a preferred embodiment, the invention relates ized in that pipamperon or said pharmaceutically acceptable to the use as described above, wherein said a compound salt thereof is administered simultaneously with, separate which is a neuroimmunophilin ligand is GPI 1485 or a pro from or prior to the administration of a selective nor-adrena drug or an active metabolite thereof, or a pharmaceutically line and dopamine re-uptake inhibitor (NDRI) compound to acceptable salt thereof. More preferably, said a compound augment the therapeutic effect or to provide a faster onset of 60 which is a neuroimmunophilin ligand is GPI 1485 and is to be the therapeutic effect of said selective nor-adrenaline and administered in a daily dose ranging between 200 and 1000 dopamine re-uptake inhibitor (NDRI) compound, further mg of the active ingredient. characterized in that pipamperon is to be administered to a The invention also relates to a pharmaceutical composition patient in a daily dose ranging between 5 and 15 mg of the comprising (a) pipamperon, and (b) a compound which is a active ingredient. 65 neuroimmunophilin ligand, preferably GPI 1485 or a pro According to a preferred embodiment, the invention relates drug or an active metabolite thereof, or a pharmaceutically to the uses as described above, wherein said selective nor acceptable salt thereof, as a combined preparation for simul US 8,304,431 B2 77 78 taneous, separate or sequential use for treating the underlying pipamperon or said pharmaceutically acceptable salt thereof emotion dysregulation of Parkinson Disease. is administered simultaneously with, separate from or prior to The invention also relates to a pharmaceutical composition the administration of a neurotensin receptor antagonist com as described above wherein pipamperon is provided in a pound to augment the therapeutic effect or to provide a faster unitary dose of between 5 and 15 mg of the active ingredient onset of the therapeutic effect of said neurotensin receptor and wherein said a compound which is a neuroimmunophilin antagonist compound, further characterized in that pipam ligand is GPI 1485, preferably provided in a unitary dose of peron is to be administered to a patient in a daily dose ranging between 200 and 1000 mg of the active ingredient. between 5 and 15 mg of the active ingredient. 64: Combination Therapy with a Neuromodulator Compound The present invention thus relates to the use of pipamperon The mental disorder which can be treated using com 10 pounds having a high selective affinity for the 5-HT2A and or a pharmaceutically acceptable salt thereof for the prepara D4 receptor, for instance pipamperon, in a combination tion of a medicament for treating the underlying emotion therapy with a neuromodulator compound, is Parkinson Dis dysregulation of pain disorders, characterized in that pipam CaSC. peron or said pharmaceutically acceptable sat thereof is The present invention thus relates to the use of pipamperon 15 administered simultaneously with, separate from or prior to or a pharmaceutically acceptable salt thereof for the prepara the administration of a neurotensin receptor antagonist com tion of a medicament for treating the underlying emotion pound to augment the therapeutic effect or to provide a faster dysregulation of Parkinson Disease, characterized in that onset of the therapeutic effect of said neurotensin receptor pipamperon or said pharmaceutically acceptable salt thereof antagonist compound, further characterized in that pipam is administered simultaneously with, separate from or prior to peron is to be administered to a patient in a daily dose ranging the administration of a neuromodulator compound to aug between 5 and 15 mg of the active ingredient. ment the therapeutic effect or to provide a faster onset of the The present invention thus relates to the use of pipamperon therapeutic effect of said neuromodulator compound, further or a pharmaceutically acceptable salt thereof for the prepara characterized in that pipamperon is to be administered to a tion of a medicament for treating the underlying emotion patient in a daily dose ranging between 5 and 15 mg of the 25 dysregulation of a cognitive mental disease or disorder which active ingredient. is delirium, characterized in that pipamperon or said pharma According to a preferred embodiment, the invention relates ceutically acceptable salt thereof is administered simulta to the use as described above, wherein said neuromodulator neously with, separate from or prior to the administration of a compound is adenosine or a pro-drug or an active metabolite neurotensin receptor antagonist compound to augment the thereof, or a pharmaceutically acceptable salt thereof. 30 The invention also relates to a pharmaceutical composition therapeutic effect or to provide a faster onset of the therapeu comprising (a) pipamperon, and (b) a neuromodulator com tic effect of said neurotensin receptor antagonist compound, pound, preferably adenosine or a pro-drug or an active further characterized in that pipamperon is to be administered metabolite thereof, or a pharmaceutically acceptable salt to a patientina daily dose ranging between 5 and 15 mg of the thereof, as a combined preparation for simultaneous, separate 35 active ingredient. or sequential use for treating the underlying emotion dysregu According to a preferred embodiment, the invention relates lation of Parkinson Disease. to the use as described above, wherein said neurotensin recep 65: Combination Therapy with a Neurotensin Receptor tor antagonist compound is SR 48692 or a pro-drug or an Antagonist Compound active metabolite thereof, or a pharmaceutically acceptable The mental disorders which can be treated using com 40 salt thereof. More preferably, said neurotensin receptor pounds having a high selective affinity for the 5-HT2A and antagonist compound is SR 48692 and is to be administered in D4 receptor, for instance pipamperon, in a combination a daily dose ranging between 90 and 300 mg of the active therapy with a neurotensin receptor antagonist compound, ingredient. are chosen from the group of diseases or disorders consisting The invention also relates to a pharmaceutical composition of mood disorders, anxiety disorders, psychotic disorders, 45 comprising (a) pipamperon, and (b) a neurotensin receptor Somatoform disorders (excluding pain disorders), factitious antagonist compound, preferably SR 48692 or a pro-drug or disorders, dissociative disorders, sleep disorders, adjustment an active metabolite thereof, or a pharmaceutically accept disorders, impulse control disorders, pervasive development able salt thereof, as a combined preparation for simultaneous, disorders, disruptive behaviour disorders, substance-related separate or sequential use for treating the underlying emotion disorders, personality disorders, psychological factors affect 50 dysregulation of a mental disease or disorder which is chosen ing medical conditions, malingering, antisocial behaviour, bereavement, occupational problem, identity problem, prob from the group consisting mood disorders, anxiety disorders, lems related to abuse or neglect, pain disorders and delirium. psychotic disorders, somatoform disorders (excluding pain The present invention thus relates to the use of pipamperon disorders), factitious disorders, dissociative disorders, sleep or a pharmaceutically acceptable salt thereof for the prepara 55 disorders, adjustment disorders, impulse control disorders, tion of a medicament for treating the underlying emotion pervasive development disorders, disruptive behaviour disor dysregulation of a non-cognitive mental disease or disorder ders, Substance-related disorders, personality disorders, psy selected from the group of diseases and disorders consisting chological factors affecting medical conditions, malingering, of mood disorders, anxiety disorders, psychotic disorders, antisocial behaviour, bereavement, occupational problem, Somatoform disorders (excluding pain disorders), factitious 60 identity problem, problems related to abuse or neglect, pain disorders, dissociative disorders, sleep disorders, adjustment disorders and delirium. disorders, impulse control disorders, pervasive development The invention also relates to a pharmaceutical composition disorders, disruptive behaviour disorders, substance-related as described above wherein pipamperon is provided in a disorders, personality disorders, psychological factors affect unitary dose of between 5 and 15 mg of the active ingredient ing medical conditions, malingering, antisocial behaviour, 65 and wherein said neurotensin receptor antagonist compound bereavement, occupational problem, identity problem and is SR 48692, preferably provided in a unitary dose of between problems related to abuse or neglect, characterized in that 90 and 300 mg of the active ingredient. US 8,304,431 B2 79 80 66: Combination Therapy with Nerve Growth Factor (NGF) instance nucleic acids used in nerve growth factor gene Gene Therapy therapy are well described (see e.g. Tuszynski et al., (2002) The mental disorders which can be treated using com Journal of Molecular Neuroscience Volume 19, Issue 1-2, pounds having a high selective affinity for the 5-HT2A and pps. 207-208). D4 receptor, for instance pipamperon, in a combination 5 67: Combination Therapy with a Nicotinic Acetylcholine therapy with nerve growth factor (NGF) gene therapy, are Receptor Antagonist Compound chosen from the group of diseases or disorders consisting of The mental disorders which can be treated using com Alzheimer Disease, Substance-induced persisting dementia, pounds having a high selective affinity for the 5-HT2A and vascular dementia, dementia due to HIV disease, dementia D4 receptor, for instance pipamperon, in a combination due to head trauma, dementia due to Parkinson Disease, 10 therapy with a nicotinic acetylcholine receptor antagonist dementia due to Huntington Disease, dementia due to Pick compound, are chosen from the group of diseases or disorders Disease, dementia due to Creutzfeldt-Jacob Disease, amnes consisting of anxiety disorders, Somatoform disorders (ex tic disorders due to a general medical condition, Substance cluding pain disorders), factitious disorders, dissociative dis induced persisting amnestic disorder, mild cognitive impair orders, adjustment disorders, impulse control disorders, Sub ment disorder, other cognitive disorders and Parkinson 15 stance-related disorders, personality disorders, bereavement, Disease. occupational problem, problems related to abuse or neglect The present invention thus relates to the use of pipamperon and pain disorders. or a pharmaceutically acceptable salt thereof for the prepara The present invention thus relates to the use of pipamperon tion of a medicament for treating the underlying emotion or a pharmaceutically acceptable salt thereof for the prepara dysregulation of a cognitive mental disease or disorder tion of a medicament for treating the underlying emotion selected from the group of diseases and disorders consisting dysregulation of a non-cognitive mental disease or disorder of Alzheimer Disease, Substance-induced persisting demen selected from the group of diseases and disorders consisting tia, Vascular dementia, dementia due to HIV disease, demen of anxiety disorders, somatoform disorders (excluding pain tia due to head trauma, dementia due to Parkinson Disease, disorders), factitious disorders, dissociative disorders, adjust dementia due to Huntington Disease, dementia due to Pick 25 ment disorders, impulse control disorders, Substance-related Disease, dementia due to Creutzfeldt-Jacob Disease, amnes disorders, personality disorders, bereavement, occupational tic disorders due to a general medical condition, Substance problem and problems related to abuse or neglect, character induced persisting amnestic disorder, mild cognitive impair ized in that pipamperon or said pharmaceutically acceptable ment disorder and other cognitive disorders, characterized in salt thereof is administered simultaneously with, separate that pipamperon or said pharmaceutically acceptable salt 30 from or prior to the administration of a nicotinic acetylcholine thereof is administered simultaneously with, separate from receptor antagonist compound to augment the therapeutic nerve growth factor (NGF) gene therapy, to augment the effect or to provide a faster onset of the therapeutic effect of therapeutic effect or to provide a faster onset of the therapeu said nicotinic acetylcholine receptor antagonist compound, tic effect of said nerve growth factor (NGF) gene therapy, further characterized in that pipamperon is to be administered further characterized in that pipamperon is to be administered 35 to a patientina daily dose ranging between 5 and 15 mg of the to a patientina daily dose ranging between 5 and 15 mg of the active ingredient. active ingredient. The present invention thus relates to the use of pipamperon The present invention thus relates to the use of pipamperon or a pharmaceutically acceptable salt thereof for the prepara or a pharmaceutically acceptable salt thereof for the prepara tion of a medicament for treating the underlying emotion tion of a medicament for treating the underlying emotion 40 dysregulation of pain disorders, characterized in that pipam dysregulation of Parkinson Disease, characterized in that peron or said pharmaceutically acceptable salt thereof is pipamperon or said pharmaceutically acceptable salt thereof administered simultaneously with, separate from or prior to is administered simultaneously with, separate from or prior to the administration of a nicotinic acetylcholine receptor nerve growth factor (NGF) gene therapy, to augment the antagonist compound to augment the therapeutic effect or to therapeutic effect or to provide a faster onset of nerve growth 45 provide a faster onset of the therapeutic effect of said nicotinic factor (NGF) gene therapy, further characterized in that acetylcholine receptor antagonist compound, further charac pipamperon is to be administered to a patient in a daily dose terized in that pipamperon is to be administered to a patient in ranging between 5 and 15 mg of the active ingredient. a daily dose ranging between 5 and 15 mg of the active The invention also relates to a pharmaceutical composition ingredient. comprising (a) pipamperon, and (b) a compound useful in 50 According to a preferred embodiment, the invention relates nerve growth factor (NGF) gene therapy, preferably Xalip to the uses as described above, wherein said nicotinic acetyl roden or a pro-drug or an active metabolite thereof, or a choline receptor antagonist compound is SEP174559 or a pharmaceutically acceptable salt thereof, as a combined pro-drug or an active metabolite thereof, or a pharmaceuti preparation for simultaneous, separate or sequential use for cally acceptable salt thereof. treating the underlying emotion dysregulation of a mental 55 The invention also relates to a pharmaceutical composition disease or disorder which is chosen from the group consisting comprising (a) pipamperon, and (b) a nicotinic acetylcholine of Alzheimer Disease, Substance-induced persisting demen receptor antagonist compound, preferably SEP174559 or a tia, Vascular dementia, dementia due to HIV disease, demen pro-drug or an active metabolite thereof, or a pharmaceuti tia due to head trauma, dementia due to Parkinson Disease, cally acceptable salt thereof, as a combined preparation for dementia due to Huntington Disease, dementia due to Pick 60 simultaneous, separate or sequential use for treating the Disease, dementia due to Creutzfeldt-Jacob Disease, amnes underlying emotion dysregulation of a mental disease or dis tic disorders due to a general medical condition, Substance order which is chosen from the group consisting of anxiety induced persisting amnestic disorder, mild cognitive impair disorders, Somatoform disorders (excluding pain disorders), ment disorder, other cognitive disorders and Parkinson factitious disorders, dissociative disorders, adjustment disor Disease. 65 ders, impulse control disorders, Substance-related disorders, It should be understood that “nerve growth factor gene personality disorders, bereavement, occupational problem, therapy' is well known in the art, and the compounds, for problems related to abuse or neglect and pain disorders. US 8,304,431 B2 81 82 68: Combination Therapy with a Nicotinic Receptor Agonist 69: Combination Therapy with a Neurokinin 2 Receptor Compound (NK2) Antagonist Compound The mental disorders which can be treated using com The mental disorders which can be treated using com pounds having a high selective affinity for the 5-HT2A and pounds having a high selective affinity for the 5-HT2A and D4 receptor, for instance pipamperon, in a combination 5 D4 receptor, for instance pipamperon, in a combination therapy with a nicotinic receptoragonist compound, are cho therapy with a neurokinin 2 receptor (NK2) antagonist com Sen from the group of diseases or disorders consisting of pound, are chosen from the group of diseases or disorders Alzheimer Disease, Substance-induced persisting dementia, consisting of mood disorders, anxiety disorders, eating dis vascular dementia, dementia due to HIV disease, dementia orders, premenstrual syndrome, Somatoform disorders (ex 10 cluding pain disorders), factitious disorders, dissociative dis due to head trauma, dementia due to Parkinson Disease, orders, sexual and gender identity disorders, sleep disorders, dementia due to Huntington Disease, dementia due to Pick adjustment disorders, impulse control disorders, Substance Disease, dementia due to Creutzfeldt-Jacob Disease, amnes related disorders, personality disorders, bereavement, occu tic disorders due to a general medical condition, Substance pational problem, problems related to abuse or neglect and induced persisting amnestic disorder, mild cognitive impair 15 pain disorders. ment disorder and other cognitive disorders. The present invention thus relates to the use of pipamperon The present invention thus relates to the use of pipamperon or a pharmaceutically acceptable salt thereof for the prepara or a pharmaceutically acceptable salt thereof for the prepara tion of a medicament for treating the underlying emotion tion of a medicament for treating the underlying emotion dysregulation of a non-cognitive mental disease or disorder dysregulation of a cognitive mental disease or disorder selected from the group of diseases and disorders consisting selected from the group of diseases and disorders consisting of mood disorders, anxiety disorders, eating disorders, pre of Alzheimer Disease, Substance-induced persisting demen menstrual syndrome, Somatoform disorders (excluding pain tia, Vascular dementia, dementia due to HIV disease, demen disorders), factitious disorders, dissociative disorders, sexual tia due to head trauma, dementia due to Parkinson Disease, and gender identity disorders, sleep disorders, adjustment dementia due to Huntington Disease, dementia due to Pick 25 disorders, impulse control disorders, Substance-related disor Disease, dementia due to Creutzfeldt-Jacob Disease, amnes ders, personality disorders, bereavement, occupational prob tic disorders due to a general medical condition, Substance lemand problems related to abuse or neglect, characterized in induced persisting amnestic disorder, mild cognitive impair that pipamperon or said pharmaceutically acceptable salt ment disorder and other cognitive disorders, characterized in thereof is administered simultaneously with, separate from or 30 prior to the administration of a neurokinin 2 receptor (NK2) that pipamperon or said pharmaceutically acceptable salt antagonist compound to augment the therapeutic effect or to thereof is administered simultaneously with, separate from or provide a faster onset of the therapeutic effect of said neuro prior to the administration of a nicotinic receptor agonist kinin 2 receptor (NK2) antagonist compound, further charac compound to augment the therapeutic effect or to provide a terized in that pipamperon is to be administered to a patient in faster onset of the therapeutic effect of said nicotinic receptor 35 a daily dose ranging between 5 and 15 mg of the active agonist compound, further characterized in that pipamperon ingredient. is to be administered to a patient in a daily dose ranging The present invention thus relates to the use of pipamperon between 5 and 15 mg of the active ingredient. or a pharmaceutically acceptable salt thereof for the prepara According to a preferred embodiment, the invention relates tion of a medicament for treating the underlying emotion to the use as described above, wherein said nicotinic receptor 40 dysregulation of pain disorders, characterized in that pipam agonist compound is ABT-089, or a pro-drug or an active peron or said pharmaceutically acceptable salt thereof is metabolite thereof, or a pharmaceutically acceptable salt administered simultaneously with, separate from or prior to thereof. More preferably, said nicotinic receptoragonist com the administration of a neurokinin 2 receptor (NK2) antago pound is ABT-089 and is to be administered in a daily dose nist compound to augment the therapeutic effect or to provide ranging between 4 and 40 mg of the active ingredient. 45 a faster onset of the therapeutic effect of said neurokinin 2 The invention also relates to a pharmaceutical composition receptor (NK2) antagonist compound, further characterized comprising (a) pipamperon, and (b) a nicotinic receptor ago in that pipamperon is to be administered to a patient in a daily nist compound, preferably ABT-089 or a pro-drug oran active dose ranging between 5 and 15 mg of the active ingredient. metabolite thereof, or a pharmaceutically acceptable salt According to a preferred embodiment, the invention relates thereof, as a combined preparation for simultaneous, separate 50 to the uses as described above, wherein said neurokinin 2 or sequential use for treating the underlying emotion dysregu receptor (NK2) antagonist compound is saredutant or a pro lation of a cognitive mental disease or disorder which is drug or an active metabolite thereof, or a pharmaceutically chosen from the group consisting of Alzheimer Disease, Sub acceptable salt thereof. More preferably, said neurokinin 2 stance-induced persisting dementia, vascular dementia, receptor (NK2) antagonist compound is saredutant and is to dementia due to HIV disease, dementia due to head trauma, 55 be administered in a daily dose ranging between 25 and 200 dementia due to Parkinson Disease, dementia due to Hunting mg of the active ingredient. ton Disease, dementia due to Pick Disease, dementia due to The invention also relates to a pharmaceutical composition Creutzfeldt-Jacob Disease, amnestic disorders due to a gen comprising (a) pipamperon, and (b) a neurokinin 2 receptor eral medical condition, Substance-induced persisting amnes (NK2) antagonist compound, preferably saredutant or a pro tic disorder, mild cognitive impairment disorder and other 60 drug or an active metabolite thereof, or a pharmaceutically cognitive disorders. acceptable salt thereof, as a combined preparation for simul The invention also relates to a pharmaceutical composition taneous, separate or sequential use for treating the underlying as described above, wherein pipamperon is provided in a emotion dysregulation of a mental disease or disorder which unitary dose of between 5 and 15 mg of the active ingredient is chosen from the group consisting of mood disorders, anxi and wherein said nicotinic receptor agonist compound is 65 ety disorders, eating disorders, premenstrual syndrome, ABT-089, preferably provided in a unitary dose of between 4 Somatoform disorders (excluding pain disorders), factitious and 40 mg of the active ingredient. disorders, dissociative disorders, sexual and gender identity US 8,304,431 B2 83 84 disorders, sleep disorders, adjustment disorders, impulse neously with, separate from or prior to the administration of a control disorders, Substance-related disorders, personality neurokinin 3 receptor (NK3) antagonist compound to aug disorders, bereavement, occupational problem, problems ment the therapeutic effect or to provide a faster onset of the related to abuse or neglect and pain disorders. therapeutic effect of said neurokinin 3 receptor (NK3) The invention also relates to a pharmaceutical composition 5 antagonist compound, further characterized in that pipam as described above wherein pipamperon is provided in a peron is to be administered to a patient in a daily dose ranging unitary dose of between 5 and 15 mg of the active ingredient between 5 and 15 mg of the active ingredient. and wherein said neurokinin 2 receptor (NK2) antagonist According to a preferred embodiment, the invention relates compound is saredutant, preferably provided in a unitary dose to the uses as described above, wherein said neurokinin 3 of between 25 and 200 mg of the active ingredient. 10 receptor (NK3) antagonist compound is talnetant or osanet 70: Combination Therapy with a Neurokinin 3 Receptor ant, or a pro-drug or an active metabolite thereof, or a phar (NK3) Antagonist Compound maceutically acceptable salt thereof. More preferably, said The mental disorders which can be treated using com neurokinin 3 receptor (NK3) antagonist compound is talnet pounds having a high selective affinity for the 5-HT2A and ant and is to be administered in a daily dose ranging between D4 receptor, for instance pipamperon, in a combination 15 1.5 and 12 mg of the active ingredient. therapy with a neurokinin 3 receptor (NK3) antagonist com The invention also relates to a pharmaceutical composition pound, are chosen from the group of diseases or disorders comprising (a) pipamperon, and (b) a neurokinin 3 receptor consisting of mood disorders, anxiety disorders, psychotic (NK3) antagonist compound, preferably talnetant or osanet disorders, Somatoform disorders (excluding pain disorders), ant, or a pro-drug or an active metabolite thereof, or a phar factitious disorders, dissociative disorders, sleep disorders, 20 maceutically acceptable salt thereof, as a combined prepara adjustment disorders, impulse control disorders, pervasive tion for simultaneous, separate or sequential use for treating development disorders, disruptive behaviour disorders, sub the underlying emotion dysregulation of a mental disease or stance-related disorders, personality disorders, psychological disorder which is chosen from the group consisting mood factors affecting medical conditions, malingering, antisocial disorders, anxiety disorders, psychotic disorders, Somato behaviour, bereavement, occupational problem, identity 25 form disorders (excluding pain disorders), factitious disor problem, problems related to abuse or neglect, pain disorders ders, dissociative disorders, sleep disorders, adjustment dis and delirium. orders, impulse control disorders, pervasive development The present invention thus relates to the use of pipamperon disorders, disruptive behaviour disorders, substance-related or a pharmaceutically acceptable salt thereof for the prepara disorders, personality disorders, psychological factors affect tion of a medicament for treating the underlying emotion 30 ing medical conditions, malingering, antisocial behaviour, dysregulation of a non-cognitive mental disease or disorder bereavement, occupational problem, identity problem, prob selected from the group of diseases and disorders consisting lems related to abuse or neglect, pain disorders and delirium. of mood disorders, anxiety disorders, psychotic disorders, The invention also relates to a pharmaceutical composition Somatoform disorders (excluding pain disorders), factitious as described above wherein pipamperon is provided in a disorders, dissociative disorders, sleep disorders, adjustment 35 unitary dose of between 5 and 15 mg of the active ingredient disorders, impulse control disorders, pervasive development and wherein said neurokinin 3 receptor (NK3) antagonist disorders, disruptive behaviour disorders, substance-related compound is talnetant, preferably provided in a unitary dose disorders, personality disorders, psychological factors affect of between 1.5 and 12 mg of the active ingredient. ing medical conditions, malingering, antisocial behaviour, 71: Combination Therapy with an N-Methyl-D-aspartate bereavement, occupational problem, identity problem and 40 (NMDA) Antagonist Compound problems related to abuse or neglect, characterized in that The mental disorders which can be treated using com pipamperon or said pharmaceutically acceptable salt thereof pounds having a high selective affinity for the 5-HT2A and is administered simultaneously with, separate from or prior to D4 receptor, for instance pipamperon, in a combination the administration of a neurokinin 3 receptor (NK3) antago therapy with an N-Methyl-D-aspartate (NMDA) antagonist nist compound to augment the therapeutic effect or to provide 45 compound, are chosen from the group of diseases or disorders a faster onset of the therapeutic effect of said neurokinin 3 consisting of mood disorders, anxiety disorders, eating dis receptor (NK3) antagonist compound, further characterized orders, premenstrual syndrome, Somatoform disorders (ex in that pipamperon is to be administered to a patient in a daily cluding pain disorders), factitious disorders, dissociative dis dose ranging between 5 and 15 mg of the active ingredient. orders, sexual and gender identity disorders, adjustment The present invention thus relates to the use of pipamperon 50 disorders, impulse control disorders, personality disorders, or a pharmaceutically acceptable salt thereof for the prepara bereavement, occupational problem, problems related to tion of a medicament for treating the underlying emotion abuse or neglect, pain disorders, Alzheimer Disease, Sub dysregulation of pain disorders, characterized in that pipam stance-related persisting dementia, Vascular dementia, peron or said pharmaceutically acceptable salt thereof is dementia due to HIV disease, dementia due to head trauma, administered simultaneously with, separate from or prior to 55 dementia due to Parkinson Disease, dementia due to Hunting the administration of a neurokinin 3 receptor (NK3) antago ton Disease, dementia due to Pick Disease, dementia due to nist compound to augment the therapeutic effect or to provide Creutzfeldt-Jacob Disease, amnestic disorders due to a gen a faster onset of the therapeutic effect of said neurokinin 3 eral medical condition, Substance-induced persisting amnes receptor (NK3) antagonist compound, further characterized tic disorder, mild cognitive impairment disorder and other in that pipamperon is to be administered to a patient in a daily 60 cognitive disorders. dose ranging between 5 and 15 mg of the active ingredient. The present invention thus relates to the use of pipamperon The present invention thus relates to the use of pipamperon or a pharmaceutically acceptable salt thereof for the prepara or a pharmaceutically acceptable salt thereof for the prepara tion of a medicament for treating the underlying emotion tion of a medicament for treating the underlying emotion dysregulation of a non-cognitive mental disease or disorder dysregulation of a cognitive mental disease or disorder which 65 selected from the group of diseases and disorders consisting is delirium, characterized in that pipamperon or said pharma of mood disorders, anxiety disorders, eating disorders, pre ceutically acceptable salt thereof is administered simulta menstrual syndrome, Somatoform disorders (excluding pain US 8,304,431 B2 85 86 disorders), factitious disorders, dissociative disorders, sexual drome. Somatoform disorders (excluding pain disorders), and gender identity disorders, adjustment disorders, impulse factitious disorders, dissociative disorders, sexual and gender control disorders, personality disorders, bereavement, occu identity disorders, adjustment disorders, impulse control dis pational problem and problems related to abuse or neglect, orders, personality disorders, bereavement, occupational characterized in that pipamperon or said pharmaceutically 5 problem, problems related to abuse or neglect, pain disorders, acceptable salt thereof is administered simultaneously with, Alzheimer Disease, Substance-related persisting dementia, separate from or prior to the administration of an N-Methyl vascular dementia, dementia due to HIV disease, dementia D-aspartate (NMDA) antagonist compound to augment the due to head trauma, dementia due to Parkinson Disease, therapeutic effect or to provide a faster onset of the therapeu dementia due to Huntington Disease, dementia due to Pick tic effect of said N-Methyl-D-aspartate (NMDA) antagonist 10 Disease, dementia due to Creutzfeldt-Jacob Disease, amnes compound, further characterized in that pipamperon is to be tic disorders due to a general medical condition, Substance administered to a patient in a daily dose ranging between 5 induced persisting amnestic disorder, mild cognitive impair and 15 mg of the active ingredient. ment disorder and other cognitive disorders. The present invention thus relates to the use of pipamperon The invention also relates to a pharmaceutical composition or a pharmaceutically acceptable salt thereof for the prepara- 15 as described above wherein pipamperon is provided in a tion of a medicament for treating the underlying emotion unitary dose of between 5 and 15 mg of the active ingredient dysregulation of pain disorders, characterized in that pipam and wherein said N-Methyl-D-aspartate (NMDA) antagonist peron or said pharmaceutically acceptable salt thereof is compound is , preferably provided in a unitary administered simultaneously with, separate from or prior to dose of between 5 and 40 mg of the active ingredient. the administration of an N-Methyl-D-aspartate (NMDA) 20 72: Combination Therapy with a Non-Steroidal Anti-Inflam antagonist compound to augment the therapeutic effect or to matory Drug provide a faster onset of the therapeutic effect of said N-Me The mental disorder which can be treated using com thyl-D-aspartate (NMDA) antagonist compound, further pounds having a high selective affinity for the 5-HT2A and characterized in that pipamperon is to be administered to a D4 receptor, for instance pipamperon, in a combination patient in a daily dose ranging between 5 and 15 mg of the 25 therapy with a non-steroidal anti-inflammatory drug, is a pain active ingredient. disorder or Alzheimer Disease. The present invention thus relates to the use of pipamperon The present invention thus relates to the use of pipamperon or a pharmaceutically acceptable salt thereof for the prepara or a pharmaceutically acceptable salt thereof for the prepara tion of a medicament for treating the underlying emotion tion of a medicament for treating the underlying emotion dysregulation of a cognitive mental disease or disorder 30 dysregulation of a pain disorder, characterized in that pipam selected from the group of diseases and disorders consisting peron or said pharmaceutically acceptable salt thereof is of Alzheimer Disease, substance-related persisting dementia, administered simultaneously with, separate from or prior to vascular dementia, dementia due to HIV disease, dementia the administration of a non-steroidal anti-inflammatory drug due to head trauma, dementia due to Parkinson Disease, to augment the therapeutic effect or to provide a faster onset dementia due to Huntington Disease, dementia due to Pick 35 of the therapeutic effect of said a non-steroidal anti-inflam Disease, dementia due to Creutzfeldt-Jacob Disease, amnes matory drug, further characterized in that pipamperon is to be tic disorders due to a general medical condition, Substance administered to a patient in a daily dose ranging between 5 induced persisting amnestic disorder, mild cognitive impair and 15 mg of the active ingredient. ment disorder and other cognitive disorders, characterized in The present invention thus relates to the use of pipamperon that pipamperon or said pharmaceutically acceptable salt 40 or a pharmaceutically acceptable salt thereof for the prepara thereof is administered simultaneously with, separate from or tion of a medicament for treating the underlying emotion prior to the administration of an N-Methyl-D-aspartate dysregulation of a cognitive disease, such as Alzheimer Dis (NMDA) antagonist compound to augment the therapeutic ease, characterized in that pipamperon or said pharmaceuti effect or to provide a faster onset of the therapeutic effect of cally acceptable salt thereof is administered simultaneously said N-Methyl-D-aspartate (NMDA) antagonist compound, 45 with, separate from or prior to the administration of a non further characterized in that pipamperon is to be administered steroidal anti-inflammatory drug to augment the therapeutic to a patientina daily dose ranging between 5 and 15 mg of the effect or to provide a faster onset of the therapeutic effect of active ingredient. said a non-steroidal anti-inflammatory drug, further charac According to a preferred embodiment, the invention relates terized in that pipamperon is to be administered to a patient in to the uses as described above, wherein said N-Methyl-D- 50 a daily dose ranging between 5 and 15 mg of the active aspartate (NMDA) antagonist compound is chosen from the ingredient. group consisting of SEP174559, memantine, delucemine, or According to a preferred embodiment, the invention relates a pro-drug or an active metabolite thereof, or a pharmaceuti to the uses as described above, wherein said a non-steroidal cally acceptable salt thereof. More preferably, said N-Me anti-inflammatory drug is chosen from the group consisting thyl-D-aspartate (NMDA) antagonist compound is meman- 55 of piroxicam, MX-1094, meloxicam and flurizan (pure tine and is to be administered in a daily dose ranging between R-enantiomerform of flurbiprofen), or a pro-drug oran active 5 and 40 mg of the active ingredient. metabolite thereof, or a pharmaceutically acceptable salt The invention also relates to a pharmaceutical composition thereof. comprising (a) pipamperon, and (b) an N-Methyl-D-aspartate The invention also relates to a pharmaceutical composition (NMDA) antagonist compound, preferably chosen from the 60 comprising (a) pipamperon, and (b) a non-steroidal anti-in group consisting of SEP174559, memantine, delucemine or a flammatory drug, preferably chosen from the group consist pro-drug or an active metabolite thereof, or a pharmaceuti ing of piroxicam, MX-1094, meloxicam and flurizan (pure cally acceptable salt thereof, as a combined preparation for R-enantiomerform of flurbiprofen), or a pro-drug oran active simultaneous, separate or sequential use for treating the metabolite thereof, or a pharmaceutically acceptable salt underlying emotion dysregulation of mental disease or disor- 65 thereof, as a combined preparation for simultaneous, separate der which is chosen from the group consisting of mood dis or sequential use for treating the underlying emotion dysregu orders, anxiety disorders, eating disorders, premenstrual Syn lation of a pain disorder or Alzheimer Disease. US 8,304,431 B2 87 88 73: Combination Therapy with an Opoid Receptor Antago problem and problems related to abuse or neglect, character nist Compound ized in that pipamperon or said pharmaceutically acceptable The mental disorders which can be treated using com salt thereof is administered simultaneously with, separate pounds having a high selective affinity for the 5-HT2A and from or prior to the administration of an opoid agonist com D4 receptor, for instance pipamperon, in a combination 5 pound to augment the therapeutic effect or to provide a faster therapy with an opoid receptor antagonist compound, are onset of the therapeutic effect of said opoid agonist com substance related disorders. pound, further characterized in that pipamperon is to be It will be appreciated that the terms “opoid’ and “opioid' administered to a patient in a daily dose ranging between 5 may be used interchangeably. and 15 mg of the active ingredient. The present invention thus relates to the use of pipamperon 10 According to a preferred embodiment, the invention relates or a pharmaceutically acceptable salt thereof for the prepara to the use as described above, wherein said opoid agonist tion of a medicament for treating the underlying emotion compound is chosen from the group consisting of siramesine, dysregulation of substance related disorders, characterized in E-5842 and cyclazocine, preferably siramesine, or a pro-drug that pipamperon or said pharmaceutically acceptable salt oran active metabolite thereof, or a pharmaceutically accept thereof is administered simultaneously with, separate from or 15 able salt thereof. prior to the administration of a opoid receptor antagonist The invention also relates to a pharmaceutical composition compound to augment the therapeutic effect or to provide a comprising (a) pipamperon, and (b) an opoid agonist com faster onset of the therapeutic effect of said opoid receptor pound, preferably chosen from the group consisting of Sir antagonist compound, further characterized in that pipam amesine, E-5842 and cyclazocine, preferably Siramesine, or a peron is to be administered to a patient in a daily dose ranging pro-drug or an active metabolite thereof, or a pharmaceuti between 5 and 15 mg of the active ingredient. cally acceptable salt thereof, as a combined preparation for According to a preferred embodiment, the invention relates simultaneous, separate or sequential use for treating the to the use as described above, wherein said opoid receptor underlying emotion dysregulation of a non-cognitive mental antagonist compound is naltrexone, preferably as a depot disease or disorder which is chosen from the group consisting formulation, more preferably in the form of microcapsules, or 25 of anxiety disorders, psychotic disorders, eating disorders, a pro-drug or an active metabolite thereof, or a pharmaceuti premenstrual syndrome, Somatoform disorders (excluding cally acceptable salt thereof. Preferably, said maltrexone is to pain disorders), factitious disorders, dissociative disorders, be administered in the form of a depot, preferably a depot of sexual and gender identity disorders, sleep disorders, adjust microcapsules comprising a daily dose of between 192 and ment disorders, impulse control disorders, Substance-related 384 mg. 30 disorders, personality disorders, bereavement, occupational The invention also relates to a pharmaceutical composition problem and problems related to abuse or neglect. comprising (a) pipamperon, and (b) an opoid receptor antago 75: Combination Therapy with a Phosphodiesterase-4 nist, preferably naltrexone, or a pro-drug oran active metabo (PDE4) Inhibitor Compound lite thereof, or a pharmaceutically acceptable Salt thereof, as The mental disorders which can be treated using com a combined preparation for simultaneous, separate or sequen 35 pounds having a high selective affinity for the 5-HT2A and tial use for treating the underlying emotion dysregulation of D4 receptor, for instance pipamperon, in a combination substance related disorders. therapy with a phosphodiesterase-4 (PDE4) inhibitor com The invention also relates to a pharmaceutical composition pound, are chosen from the group of diseases or disorders as described above wherein pipamperon is provided in a consisting of mood disorders, anxiety disorders, eating dis unitary dose of between 5 and 15 mg of the active ingredient 40 orders, premenstrual syndrome, Somatoform disorders (ex and wherein said opoid receptor antagonist compound is nal cluding pain disorders), factitious disorders, dissociative dis trexone, preferably provided in a unitary dose of between 192 orders, sexual and gender identity disorders, adjustment and 384 mg of the active ingredient. disorders, impulse control disorders, personality disorders, 74: Combination Therapy with an Opoid Agonist Compound bereavement, occupational problem, problems related to The mental disorders which can be treated using com 45 abuse or neglect, pain disorders, Alzheimer Disease, Sub pounds having a high selective affinity for the 5-HT2A and stance-related persisting dementia, Vascular dementia, D4 receptor, for instance pipamperon, in a combination dementia due to HIV disease, dementia due to head trauma, therapy with an opoid agonist compound, are chosen from the dementia due to Parkinson Disease, dementia due to Hunting group of diseases or disorders consisting of anxiety disorders, ton Disease, dementia due to Pick Disease, dementia due to psychotic disorders, eating disorders, premenstrual Syn 50 Creutzfeldt-Jacob Disease, amnestic disorders due to a gen drome. Somatoform disorders (excluding pain disorders), fac eral medical condition, Substance-induced persisting amnes titious disorders, dissociative disorders, sexual and gender tic disorder, mild cognitive impairment disorder and other identity disorders, sleep disorders, adjustment disorders, cognitive disorders. impulse control disorders, Substance-related disorders, per The present invention thus relates to the use of pipamperon Sonality disorders, bereavement, occupational problem and 55 or a pharmaceutically acceptable salt thereof for the prepara problems related to abuse or neglect. tion of a medicament for treating the underlying emotion The present invention thus relates to the use of pipamperon dysregulation of a non-cognitive mental disease or disorder or a pharmaceutically acceptable salt thereof for the prepara selected from the group of diseases and disorders consisting tion of a medicament for treating the underlying emotion of mood disorders, anxiety disorders, eating disorders, pre dysregulation of a non-cognitive mental disease or disorder 60 menstrual syndrome, Somatoform disorders (excluding pain selected from the group of diseases and disorders consisting disorders), factitious disorders, dissociative disorders, sexual of anxiety disorders, psychotic disorders, eating disorders, and gender identity disorders, adjustment disorders, impulse premenstrual syndrome, Somatoform disorders (excluding control disorders, personality disorders, bereavement, occu pain disorders), factitious disorders, dissociative disorders, pational problem and problems related to abuse or neglect, sexual and gender identity disorders, sleep disorders, adjust 65 characterized in that pipamperon or said pharmaceutically ment disorders, impulse control disorders, Substance-related acceptable salt thereof is administered simultaneously with, disorders, personality disorders, bereavement, occupational separate from or prior to the administration of phosphodi US 8,304,431 B2 89 90 esterase-4 (PDE4) inhibitor compound to augment the thera stance-induced persisting amnestic disorder, mild cognitive peutic effect or to provide a faster onset of the therapeutic impairment disorder and other cognitive disorders. effect of said phosphodiesterase-4 (PDE4) inhibitor com 76: Combination Therapy with a Peptidic Compound pound, further characterized in that pipamperon is to be The mental disorders which can be treated using com administered to a patient in a dally dose ranging between 5 pounds having a high selective affinity for the 5-HT2A and and 15 mg of the active ingredient. D4 receptor, for instance pipamperon, in a combination The present invention thus relates to the use of pipamperon therapy with a peptidic compound, are chosen from the group or a pharmaceutically acceptable salt thereof for the prepara of diseases or disorders consisting of mood disorders, anxiety tion of a medicament for treating the underlying emotion disorders, eating disorders, premenstrual syndrome, Somato dysregulation of pain disorders, characterized in that pipam 10 form disorders (excluding pain disorders), factitious disor peron or said pharmaceutically acceptable salt thereof is ders, dissociative disorders, sexual and gender identity disor administered simultaneously with, separate from or prior to ders, sleep disorders, adjustment disorders, impulse control the administration of a phosphodiesterase-4 (PDE4) inhibitor disorders, pervasive development disorders, disruptive compound d to augment the therapeutic effect or to provide a behaviour disorders, Substance related disorders, personality faster onset of the therapeutic effect of said phosphodi 15 disorders, bereavement, occupational problem, problems esterase-4 (PDE4) inhibitor compound, further characterized related to abuse or neglect, pain disorders, Alzheimer Dis in that pipamperon is to be administered to a patient in a daily ease, Substance-induced persisting dementia, Vascular dose ranging between 5 and 15 mg of the active ingredient. dementia, dementia due to HIV disease, dementia due to head The present invention thus relates to the use of pipamperon trauma, dementia due to Parkinson Disease, dementia due to or a pharmaceutically acceptable salt thereof for the prepara Huntington Disease, dementia due to Pick Disease, dementia tion of a medicament for treating the underlying emotion due to Creutzfeldt-Jacob Disease, amnestic disorders due to a dysregulation of a cognitive mental disease or disorder general medical condition, Substance-induced persisting selected from the group of diseases and disorders consisting amnestic disorder, mild cognitive impairment disorder and of Alzheimer Disease, Substance-related persisting dementia, other cognitive disorders. vascular dementia, dementia due to HIV disease, dementia 25 The present invention thus relates to the use of pipamperon due to head trauma, dementia due to Parkinson Disease, or a pharmaceutically acceptable salt thereof for the prepara dementia due to Huntington Disease, dementia due to Pick tion of a medicament for treating the underlying emotion Disease, dementia due to Creutzfeldt-Jacob Disease, amnes dysregulation of a non-cognitive mental disease or disorder tic disorders due to a general medical condition, Substance selected from the group of diseases and disorders consisting induced persisting amnestic disorder, mild cognitive impair 30 of mood disorders, anxiety disorders, eating disorders, pre ment disorder and other cognitive disorders, characterized in menstrual syndrome, Somatoform disorders (excluding pain that pipamperon or said pharmaceutically acceptable salt disorders), factitious disorders, dissociative disorders, sexual thereof is administered simultaneously with, separate from or and gender identity disorders, sleep disorders, adjustment prior to the administration of a phosphodiesterase-4 (PDE4) disorders, impulse control disorders, pervasive development inhibitor compound to augment the therapeutic effect or to 35 disorders, disruptive behaviour disorders, substance related provide a faster onset of the therapeutic effect of said phos disorders, personality disorders, bereavement, occupational phodiesterase-4 (PDE4) inhibitor compound, further charac problem and problems related to abuse or neglect, character terized in that pipamperon is to be administered to a patient in ized in that pipamperon or said pharmaceutically acceptable a daily dose ranging between 5 and 15 mg of the active salt thereof is administered simultaneously with, separate ingredient. 40 from or prior to the administration of a peptidic compound to According to a preferred embodiment, the invention relates augment the therapeutic effect or to provide a faster onset of to the uses as described above, wherein said phosphodi the therapeutic effect of said peptidic compound, further esterase-4 (PDE4) inhibitor compound is chosen from the characterized in that pipamperon is to be administered to a group consisting of ND1251 and MEM1917 (R1497), or a patient in a daily dose ranging between 5 and 15 mg of the pro-drug or an active metabolite thereof, or a pharmaceuti 45 active ingredient. cally acceptable salt thereof. The present invention thus relates to the use of pipamperon The invention also relates to a pharmaceutical composition or a pharmaceutically acceptable salt thereof for the prepara comprising (a) pipamperon, and (b) a phosphodiesterase-4 tion of a medicament for treating the underlying emotion (PDE4) inhibitor antagonist compound, preferably chosen dysregulation of pain disorders, characterized in that pipam from the group consisting of ND1251 and MEM 1917 50 peron or said pharmaceutically acceptable salt thereof is (R1497), or a pro-drug or an active metabolite thereof, or a administered simultaneously with, separate from or prior to pharmaceutically acceptable salt thereof, as a combined the administration of a peptidic compound to augment the preparation for simultaneous, separate or sequential use for therapeutic effect or to provide a faster onset of the therapeu treating the underlying emotion dysregulation of mental dis tic effect of said peptidic compound, further characterized in ease or disorder which is chosen from the group consisting of 55 that pipamperon is to be administered to a patient in a daily mood disorders, anxiety disorders, eating disorders, premen dose ranging between 5 and 15 mg of the active ingredient. strual syndrome, Somatoform disorders (excluding pain dis The present invention thus relates to the use of pipamperon orders), factitious disorders, dissociative disorders, sexual or a pharmaceutically acceptable salt thereof for the prepara and gender identity disorders, adjustment disorders, impulse tion of a medicament for treating the underlying emotion control disorders, personality disorders, bereavement, occu 60 dysregulation of a cognitive mental disease or disorder pational problem, problems related to abuse or neglect, pain selected from the group of diseases and disorders consisting disorders, Alzheimer Disease, Substance-related persisting of Alzheimer Disease, Substance-induced persisting demen dementia, Vascular dementia, dementia due to HIV disease, tia, Vascular dementia, dementia due to HIV disease, demen dementia due to head trauma, dementia due to Parkinson tia due to head trauma, dementia due to Parkinson Disease, Disease, dementia due to Huntington Disease, dementia due 65 dementia due to Huntington Disease, dementia due to Pick to Pick Disease, dementia due to Creutzfeldt-Jacob Disease, Disease, dementia due to Creutzfeldt-Jacob Disease, amnes amnestic disorders due to a general medical condition, Sub tic disorders due to a general medical condition, Substance US 8,304,431 B2 91 92 induced persisting amnestic disorder, mild cognitive impair syndrome, Somatoform disorders (excluding pain disorders), ment disorder and other cognitive disorders, characterized in factitious disorders, dissociative disorders, sexual and gender that pipamperon or said pharmaceutically acceptable salt identity disorders, sleep disorders, adjustment disorders, thereof is administered simultaneously with, separate from or impulse control disorders, pervasive development disorders, prior to the administration of a peptidic compound to aug 5 disruptive behaviour disorders, substance-related disorders, ment the therapeutic effect or to provide a faster onset of the personality disorders, bereavement, occupational problem, therapeutic effect of said peptidic compound, further charac problems related to abuse or neglect, pain disorders and terized in that pipamperon is to be administered to a patient in delirium. a daily dose ranging between 5 and 15 mg of the active The present invention thus relates to the use of pipamperon ingredient. 10 or a pharmaceutically acceptable salt thereof for the prepara According to a preferred embodiment, the invention relates tion of a medicament for treating the underlying emotion to the uses as described above, wherein said peptidic com dysregulation of a non-cognitive mental disease or disorder pound is chosen from the group consisting of secretin, selected from the group of diseases and disorders consisting PT-141, INN 00835 and beta sheet breaker peptide, or a of mood disorders, anxiety disorders, psychotic disorders, pro-drug or an active metabolite thereof, or a pharmaceuti 15 eating disorders, premenstrual syndrome, Somatoform disor cally acceptable salt thereof. More preferably, said peptidic ders (excluding pain disorders), factitious disorders, disso compound is secretin and is to be administered in a daily dose ciative disorders, sexual and gender identity disorders, sleep ranging between 0.2 and 0.4 mg/kg of the active ingredient. disorders, adjustment disorders, impulse control disorders, More preferably, said peptidic compound is INN 00835 and is pervasive development disorders, disruptive behaviour disor to be administered in a daily dose ranging between 18 and 160 ders, Substance-related disorders, personality disorders, mg of the active ingredient. bereavement, occupational problem and problems related to The invention also relates to a pharmaceutical composition abuse or neglect, characterized in that pipamperon or said comprising (a) pipamperon, and (b) a peptidic compound, pharmaceutically acceptable salt thereof is administered preferably chosen from the group consisting of secretin, simultaneously with, separate from or prior to the adminis PT-141, INN 00835 and beta sheet breaker peptide, or a 25 tration of a phospholipase A2 inhibitor compound which has pro-drug or an active metabolite thereof, or a pharmaceuti caspase inhibitor activity to augment the therapeutic effect or cally acceptable salt thereof, as a combined preparation for to provide a faster onset of the therapeutic effect of said simultaneous, separate or sequential use for treating the phospholipase A2 inhibitor compound which has caspase underlying emotion dysregulation of mental disease or disor inhibitor activity, further characterized in that pipamperon is der which is chosen from the group consisting of mood dis 30 to be administered to a patient in a daily dose ranging between orders, anxiety disorders, eating disorders, premenstrual Syn 5 and 15 mg of the active ingredient. drome, somatoform disorders (excluding pain disorders), The present invention thus relates to the use of pipamperon factitious disorders, dissociative disorders, sexual and gender or a pharmaceutically acceptable salt thereof for the prepara identity disorders, sleep disorders, adjustment disorders, tion of a medicament for treating the underlying emotion impulse control disorders, pervasive development disorders, 35 dysregulation of pain disorders, characterized in that pipam disruptive behaviour disorders, substance related disorders, peron or said pharmaceutically acceptable salt thereof is personality disorders, bereavement, occupational problem, administered simultaneously with, separate from or prior to problems related to abuse or neglect, pain disorders, Alzhe the administration of a phospholipase A2 inhibitor compound imer Disease, Substance-induced persisting dementia, Vascu which has caspase inhibitor activity to augment the therapeu lar dementia, dementia due to HIV disease, dementia due to 40 tic effect or to provide a faster onset of the therapeutic effect head trauma, dementia due to Parkinson Disease, dementia of said phospholipase A2 inhibitor compound which has due to Huntington Disease, dementia due to Pick Disease, caspase inhibitor activity, further characterized in that pipam dementia due to Creutzfeldt-Jacob Disease, amnestic disor peron is to be administered to a patient in a daily dose ranging ders due to a general medical condition, Substance-induced between 5 and 15 mg of the active ingredient. persisting amnestic disorder, mild cognitive impairment dis 45 The present invention thus relates to the use of pipamperon order and other cognitive disorders. or a pharmaceutically acceptable salt thereof for the prepara The invention also relates to a pharmaceutical composition tion of a medicament for treating the underlying emotion as described above wherein pipamperon is provided in a dysregulation of a cognitive mental disease or disorder which unitary dose of between 5 and 15 mg of the active ingredient is delirium, characterized in that pipamperon or said pharma and wherein said peptidic compound is secretin, preferably 50 ceutically acceptable salt thereof is administered simulta provided in a unitary dose of 0.2 and 0.4 mg/kg of the active neously with, separate from or prior to the administration of a ingredient. phospholipase A2 inhibitor compound which has caspase The invention also relates to a pharmaceutical composition inhibitor activity to augment the therapeutic effect or to pro as described above wherein pipamperon is provided in a vide a faster onset of the therapeutic effect of said phospho unitary dose of between 5 and 15 mg of the active ingredient 55 lipase A2 inhibitor compound which has caspase inhibitor and wherein said peptidic compound is INN 00835, prefer activity, further characterized in that pipamperon is to be ably provided in a unitary dose of 18 and 160 mg of the active administered to a patient in a daily dose ranging between 5 ingredient. and 15 mg of the active ingredient. 77: Combination Therapy with a Phospholipase A2 Inhibitor According to a preferred embodiment, the invention relates Compound 60 to the uses as described above, wherein said phospholipase The mental disorders which can be treated using com A2 inhibitor compound which has caspase inhibitor activity pounds having a high selective affinity for the 5-HT2A and is chosen from the group consisting of LAX-101a, LAX-101b D4 receptor, for instance pipamperon, in a combination and LAX-101c, preferably LAX-101c, or a pro-drug or an therapy with a phospholipase A2 inhibitor compound which active metabolite thereof, or a pharmaceutically acceptable has caspase inhibitor activity, are chosen from the group of 65 salt thereof. diseases or disorders consisting of mood disorders, anxiety The invention also relates to a pharmaceutical composition disorders, psychotic disorders, eating disorders, premenstrual comprising (a) pipamperon, and (b) a phospholipase A2 US 8,304,431 B2 93 94 inhibitor compound which has caspase inhibitor activity, is a prodrug of uridine is RG2133 (triacetyluridine) or a preferably chosen from the group consisting of LAX-101a, pro-drug or an active metabolite thereof, or a pharmaceuti LAX-101b and LAX-101c, more preferably LAX-101c, or a cally acceptable salt thereof. pro-drug or an active metabolite thereof, or a pharmaceuti The invention also relates to a pharmaceutical composition cally acceptable salt thereof, as a combined preparation for comprising (a) pipamperon, and (b) a compound which is a simultaneous, separate or sequential use for treating the prodrug of uridine, preferably RG2133 (triacetyluridine) or a underlying emotion dysregulation of a mental disease or dis pro-drug or an active metabolite thereof, or a pharmaceuti order which is chosen from the group consisting mood disor cally acceptable salt thereof, as a combined preparation for ders, anxiety disorders, psychotic disorders, eating disorders, simultaneous, separate or sequential use for treating the 10 underlying emotion dysregulation of a mental disease or dis premenstrual syndrome, Somatoform disorders (excluding order which is chosen from the group consisting of mood pain disorders), factitious disorders, dissociative disorders, disorders, anxiety disorders, eating disorders, premenstrual sexual and gender identity disorders, sleep disorders, adjust syndrome, Somatoform disorders (excluding pain disorders), ment disorders, impulse control disorders, pervasive devel factitious disorders, dissociative disorders, sexual and gender opment disorders, disruptive behaviour disorders, Substance 15 identity disorders, sleep disorders, adjustment disorders, related disorders, personality disorders, bereavement, impulse control disorders, personality disorders, bereave occupational problem, problems related to abuse or neglect, ment, occupational problem, problems related to abuse or pain disorders and delirium. neglect and pain disorders. 78: Combination Therapy with a Compound which is a Pro 79: Combination Therapy with Prostaglandin E1 Compound drug of Uridine The mental disorders which can be treated using com The mental disorders which can be treated using com pounds having a high selective affinity for the 5-HT2A and pounds having a high selective affinity for the 5-HT2A and D4 receptor, for instance pipamperon, in a combination D4 receptor, for instance pipamperon, in a combination therapy with prostaglandin E1 compound, are sexual and therapy with a compound which is a prodrug of uridine, are gender identity disorders. chosen from the group of diseases or disorders consisting of 25 The present invention thus relates to the use of pipamperon mood disorders, anxiety disorders, eating disorders, premen or a pharmaceutically acceptable salt thereof for the prepara strual syndrome, Somatoform disorders (excluding pain dis tion of a medicament for treating the underlying emotion orders), factitious disorders, dissociative disorders, sexual dysregulation of a non-cognitive mental disease or disorder and gender identity disorders, sleep disorders, adjustment selected from the group of sexual and gender identity disor ders, characterized in that pipamperon or said pharmaceuti disorders, impulse control disorders, personality disorders, cally acceptable salt thereof is administered simultaneously bereavement, occupational problem, problems related to with, separate from or prior to the administration of a pros abuse or neglect and pain disorders. taglandin E1 compound to augment the therapeutic effect or The present invention thus relates to the use of pipamperon to provide a faster onset of the therapeutic effect of said or a pharmaceutically acceptable salt thereof for the prepara 35 prostaglandin E1 compound, further characterized in that tion of a medicament for treating the underlying emotion pipamperon is to be administered to a patient in a daily dose dysregulation of a non-cognitive mental disease or disorder ranging between 5 and 15 mg of the active ingredient. selected from the group of diseases and disorders consisting According to a preferred embodiment, the invention relates of mood disorders, anxiety disorders, eating disorders, pre to the use as described above, wherein said prostaglandin E1 menstrual syndrome, Somatoform disorders (excluding pain 40 is alprostadil or a pro-drug or an active metabolite thereof, or disorders), factitious disorders, dissociative disorders, sexual a pharmaceutically acceptable salt thereof. More preferably, and gender identity disorders, sleep disorders, adjustment said prostaglandin E1 compound is alprostadil, preferably in disorders, impulse control disorders, personality disorders, the form of cream or gel, preferably a topical gel, and is to be bereavement, occupational problem and problems related to administered in a daily dose ranging between 50 and 300 abuse or neglect, characterized in that pipamperon or said 45 microgram per application of the active ingredient. pharmaceutically acceptable salt thereof is administered The invention also relates to a pharmaceutical composition simultaneously with, separate from or prior to the adminis comprising (a) pipamperon, and (b) a prostaglandin E1 com tration of a compound which is a prodrug of uridine to aug pound, preferably alprostadil or a pro-drug or an active ment the therapeutic effect or to provide a faster onset of the metabolite thereof, or a pharmaceutically acceptable salt therapeutic effect of said compound which is a prodrug of 50 thereof, as a combined preparation for simultaneous, separate uridine, further characterized in that pipamperon is to be or sequential use for treating the underlying emotion dysregu administered to a patient in a daily dose ranging between 5 lation of amental disease or disorder which is chosen from the and 15 mg of the active ingredient. group of sexual and gender identity disorders. The present invention thus relates to the use of pipamperon The invention also relates to a pharmaceutical composition or a pharmaceutically acceptable salt thereof for the prepara 55 as described above wherein pipamperon is provided in a tion of a medicament for treating the underlying emotion unitary dose of between 5 and 15 mg of the active ingredient dysregulation of pain disorders, characterized in that pipam and wherein said prostaglandin E1 compound is alprostadil, peron or said pharmaceutically acceptable salt thereof is preferably provided in the form of a cream or gel, preferably administered simultaneously with, separate from or prior to a topical gel, wherein a unitary dose comprises between 50 the administration of a compound which is a prodrug of 60 and 300 microgram of the active ingredient per application. uridine to augment the therapeutic effect or to provide a faster 80: Combination Therapy with a Compound Protecting onset of the therapeutic effect of said compound which is a Dopaminergic and Cholinergic Neurons prodrug of uridine, further characterized in that pipamperon The mental disorders which can be treated using com is to be administered to a patient in a daily dose ranging pounds having a high selective affinity for the 5-HT2A and between 5 and 15 mg of the active ingredient. 65 D4 receptor, for instance pipamperon, in a combination According to a preferred embodiment, the invention relates therapy with a compound which protects dopaminergic and to the uses as described above, wherein said compound which cholinergic neurons, are chosen from the group of diseases or US 8,304,431 B2 95 96 disorders consisting of Alzheimer Disease, Substance-in 81: Combination Therapy with a Psycho Stimulant duced persisting dementia, Vascular dementia, dementia due The mental disorders which can be treated using com to HIV disease, dementia due to head trauma, dementia due to pounds having a high selective affinity for the 5-HT2A and Parkinson Disease, dementia due to Huntington Disease, D4 receptor, for instance pipamperon, in a combination therapy with a psycho Stimulant, are chosen from the group of dementia due to Pick Disease, dementia due to Creutzfeldt diseases or disorders consisting of sleep disorders, attention Jacob Disease, amnestic disorders due to a general medical deficit disorders and substance-related disorders. condition, Substance-induced persisting amnestic disorder, The present invention thus relates to the use of pipamperon mild cognitive impairment disorder, other cognitive disorders or a pharmaceutically acceptable salt thereof for the prepara and Parkinson Disease. tion of a medicament for treating the underlying emotion The present invention thus relates to the use of pipamperon 10 dysregulation of a non-cognitive mental disease or disorder or a pharmaceutically acceptable salt thereof for the prepara selected from the group of diseases and disorders consisting tion of a medicament for treating the underlying emotion of sleep disorders, attention-deficit disorders and Substance dysregulation of a cognitive mental disease or disorder related disorders, characterized in that pipamperon or said pharmaceutically acceptable salt thereof is administered selected from the group of diseases and disorders consisting 15 simultaneously with, separate from or prior to the adminis of Alzheimer Disease, Substance-induced persisting demen tration of a psycho Stimulant to augment the therapeutic effect tia, Vascular dementia, dementia due to HIV disease, demen or to provide a faster onset of the therapeutic effect of said tia due to head trauma, dementia due to Parkinson Disease, psycho Stimulant, further characterized in that pipamperon is dementia due to Huntington Disease, dementia due to Pick to be administered to a patient in a daily dose ranging between Disease, dementia due to Creutzfeldt-Jacob Disease, amnes 5 and 15 mg of the active ingredient. tic disorders due to a general medical condition, Substance According to a preferred embodiment, the invention relates induced persisting amnestic disorder, mild cognitive impair to the uses as described above, wherein said psycho Stimulant ment disorder and other cognitive disorders, characterized in is chosen from the group consisting of SPD 503, r-modafinil that pipamperon or said pharmaceutically acceptable salt and modafinil, or a pro-drug or an active metabolite thereof, thereof is administered simultaneously with, separate from or 25 or a pharmaceutically acceptable salt thereof. More prefer prior to the administration of a compound which protects ably, said psycho stimulant is SPE 503, more preferably said dopaminergic and cholinergic neurons to augment the thera psycho Stimulant is modafinil and is to be administered in a peutic effect or to provide a faster onset of the therapeutic daily dose ranging between 200 and 600 mg of the active effect of said compound which protects dopaminergic and ingredient. cholinergic neurons, further characterized in that pipamperon 30 The invention also relates to a pharmaceutical composition is to be administered to a patient in a daily dose ranging comprising (a) pipamperon, and (b) a psycho Stimulant, pref between 5 and 15 mg of the active ingredient. erably chosen from the group consisting of SPD 503, The present invention thus relates to the use of pipamperon r-modafinil and modafinil, more preferably said SPC 503 or or a pharmaceutically acceptable salt thereof for the prepara modafinil or a pro-drug or an active metabolite thereof, or a tion of a medicament for treating the underlying emotion 35 pharmaceutically acceptable salt thereof, as a combined dysregulation of Parkinson Disease, characterized in that preparation for simultaneous, separate or sequential use for pipamperon or said pharmaceutically acceptable salt thereof treating the underlying emotion dysregulation of a non-cog is administered simultaneously with, separate from or prior to nitive mental disease or disorder which is chosen from the the administration of a compound which protects dopamin group consisting of sleep disorders, attention-deficit disor ergic and cholinergic neurons to augment the therapeutic 40 ders and Substance-related disorders. effect or to provide a faster onset of the therapeutic effect of The invention also relates to a pharmaceutical composition said compound which protects dopaminergic and cholinergic as described above wherein pipamperon is provided in a neurons, further characterized in that pipamperon is to be unitary dose of between 5 and 15 mg of the active ingredient administered to a patient in a daily dose ranging between 5 and wherein said psycho stimulant is modafinil, preferably and 15 mg of the active ingredient. 45 provided in a unitary dose of between 200 and 600 mg of the According to a preferred embodiment, the invention relates active ingredient. to the uses as described above, wherein said compound which 82: Combination Therapy with a Compound which is a protects dopaminergic and cholinergic neurons is SR 57667 Reversible Inhibitor of Mono-Amine Oxydase A (RIMA) or a pro-drug or an active metabolite thereof, or a pharma The mental disorders which can be treated using com ceutically acceptable salt thereof. 50 pounds having a high selective affinity for the 5-HT2A and The invention also relates to a pharmaceutical composition D4 receptor, for instance pipamperon, in a combination comprising (a) pipamperon, and (b) a compound which pro therapy with a compound which is a reversible inhibitor of tects dopaminergic and cholinergic neurons, preferably SR mono-amine oxydase A (RIMA), are chosen from the group 57667 or a pro-drug or an active metabolite thereof, or a of diseases or disorders consisting of mood disorders, anxiety pharmaceutically acceptable salt thereof, as a combined 55 disorders, eating disorders, premenstrual syndrome, Somato preparation for simultaneous, separate or sequential use for form disorders (excluding pain disorders), factitious disor treating the underlying emotion dysregulation of a mental ders, dissociative disorders, sexual and gender identity disor disease or disorder which is chosen from the group consisting ders, adjustment disorders, impulse control disorders, of Alzheimer Disease, Substance-induced persisting demen personality disorders, antisocial behaviour, bereavement, tia, Vascular dementia, dementia due to HIV disease, demen 60 occupational problem, problems related to abuse or neglect tia due to head trauma, dementia due to Parkinson Disease, and pain disorders. dementia due to Huntington Disease, dementia due to Pick The present invention thus relates to the use of pipamperon Disease, dementia due to Creutzfeldt-Jacob Disease, amnes or a pharmaceutically acceptable salt thereof for the prepara tic disorders due to a general medical condition, Substance tion of a medicament for treating the underlying emotion induced persisting amnestic disorder, mild cognitive impair 65 dysregulation of a non-cognitive mental disease or disorder ment disorder, other cognitive disorders and Parkinson selected from the group of diseases and disorders consisting Disease. of mood disorders, anxiety disorders, eating disorders, pre US 8,304,431 B2 97 98 menstrual syndrome, Somatoform disorders (excluding pain D4 receptor, for instance pipamperon, in a combination disorders), factitious disorders, dissociative disorders, sexual therapy with a compound which modulates SCT-11 (i.e. SCT and gender identity disorders, adjustment disorders, impulse 11 is a G protein-coupled receptor), are chosen from the control disorders, personality disorders, antisocial behaviour, group of diseases or disorders consisting of mood disorders, bereavement, occupational problem and problems related to anxiety disorders, eating disorders, premenstrual syndrome, abuse or neglect, characterized in that pipamperon or said Somatoform disorders (excluding pain disorders), factitious pharmaceutically acceptable salt thereof is administered disorders, dissociative disorders, sexual and gender identity simultaneously with, separate from or prior to the adminis disorders, sleep disorders, adjustment disorders, impulse tration of a compound which is a reversible inhibitor of mono control disorders, personality disorders, bereavement, occu amine oxydase A (RIMA) to augment the therapeutic effector 10 pational problem, problems related to abuse or neglect and to provide a faster onset of the therapeutic effect of said pain disorders. compound which is a reversible inhibitor of mono-amine The present invention thus relates to the use of pipamperon oxydase A (RIMA), further characterized in that pipamperon or a pharmaceutically acceptable salt thereof for the prepara is to be administered to a patient in a daily dose ranging tion of a medicament for treating the underlying emotion between 5 and 15 mg of the active ingredient. 15 dysregulation of a non-cognitive mental disease or disorder The present invention thus relates to the use of pipamperon selected from the group of diseases and disorders consisting or a pharmaceutically acceptable salt thereof for the prepara of mood disorders, anxiety disorders, eating disorders, pre tion of a medicament for treating the underlying emotion menstrual syndrome, Somatoform disorders (excluding pain dysregulation of pain disorders, characterized in that pipam disorders), factitious disorders, dissociative disorders, sexual peron or said pharmaceutically acceptable salt thereof is and gender identity disorders, sleep disorders adjustment dis administered simultaneously with, separate from or prior to orders, impulse control disorders, personality disorders, the administration of a compound which is a reversible inhibi bereavement, occupational problem and problems related to tor of mono-amine oxydase A (RIMA) to augment the thera abuse or neglect, characterized in that pipamperon or said peutic effect or to provide a faster onset of the therapeutic pharmaceutically acceptable salt thereof is administered effect of said compound which is a reversible inhibitor of 25 simultaneously with, separate from or prior to the adminis mono-amine oxydase A (RIMA), further characterized in that tration of a compound which modulates SCT-11 to augment pipamperon is to be administered to a patient in a daily dose the therapeutic effect or to provide a faster onset of the thera ranging between 5 and 15 mg of the active ingredient. peutic effect of said compound which modulates SCT-11, According to a preferred embodiment, the invention relates further characterized in that pipamperon is to be administered to the uses as described above, wherein said compound which 30 to a patientina daily dose ranging between 5 and 15 mg of the is a reversible inhibitor of mono-amine oxydase A (RIMA) is active ingredient. chosen from the group consisting of toloxatone, RS 8359, The present invention thus relates to the use of pipamperon moclobemide, cimoxatone, caroxazone (FJ 6654) and or a pharmaceutically acceptable salt thereof for the prepara befloxatone, or a pro-drug or an active metabolite thereof, or tion of a medicament for treating the underlying emotion a pharmaceutically acceptable salt thereof. More preferably, 35 dysregulation of pain disorders, characterized in that pipam said compound which is a reversible inhibitor of mono-amine peron or said pharmaceutically acceptable salt thereof is oxydase A (RIMA) is befloxatone and is to be administered in administered simultaneously with, separate from or prior to a daily dose ranging between 2.5 and 20 mg of the active the administration of a compound which modulates SCT-11 ingredient. to augment the therapeutic effect or to provide a faster onset The invention also relates to a pharmaceutical composition 40 of the therapeutic effect of said compound which modulates comprising (a) pipamperon, and (b) a compound which is a SCT-11, further characterized in that pipamperon is to be reversible inhibitor of mono-amine oxydase A (RIMA), pref administered to a patient in a daily dose ranging between 5 erably chosen from the group consisting of toloxatone, RS and 15 mg of the active ingredient. 8359, moclobemide, cimoxatone, caroxazone (FJ 6654) and According to a preferred embodiment, the invention relates befloxatone, or a pro-drug or an active metabolite thereof, or 45 to the use as described above, wherein said compound which a pharmaceutically acceptable salt thereof, as a combined modulates SCT-11 is SNEC-2 or a pro-drug or an active preparation for simultaneous, separate or sequential use for metabolite thereof, or a pharmaceutically acceptable salt treating the underlying emotion dysregulation of mental dis thereof. ease or disorder which is chosen from the group consisting of The invention also relates to a pharmaceutical composition mood disorders, anxiety disorders, eating disorders, premen 50 comprising (a) pipamperon, and (b) a compound which strual syndrome, Somatoform disorders (excluding pain dis modulates SCT-11, preferably SNE-2 or a pro-drug or an orders), factitious disorders, dissociative disorders, sexual active metabolite thereof, or a pharmaceutically acceptable and gender identity disorders, adjustment disorders, impulse salt thereof, as a combined preparation for simultaneous, control disorders, personality disorders, antisocial behaviour, separate or sequential use for treating the underlying emotion bereavement, occupational problem, problems related to 55 dysregulation of a mental disease or disorder which is chosen abuse or neglect and pain disorders. from the group consisting of mood disorders, anxiety disor The invention also relates to a pharmaceutical composition ders, eating disorders, premenstrual syndrome, Somatoform as described above wherein pipamperon is provided in a disorders (excluding pain disorders), factitious disorders, dis unitary dose of between 5 and 15 mg of the active ingredient Sociative disorders, sexual and gender identity disorders, and wherein said compound which is a reversible inhibitor of 60 sleep disorders, adjustment disorders, impulse control disor mono-amine oxydase A (RIMA) is befloxatone, preferably ders, personality disorders, bereavement, occupational prob provided in a unitary dose of between 2.5 and 20 mg of the lem, problems related to abuse or neglect and pain disorders. active ingredient. 84: Combination Therapy with a Serotonin/Dopamine 83: Combination Therapy with a Compound which Modu Antagonist Compound (SDA) lates SCT-11 65 The mental disorders which can be treated using com The mental disorders which can be treated using com pounds having a high selective affinity for the 5-HT2A and pounds having a high selective affinity for the 5-HT2A and D4 receptor, for instance pipamperon, in a combination US 8,304,431 B2 99 100 therapy with a serotonin/dopamine antagonist compound BSF-190555, , bifeprunox, and arip (SDA), are chosen from the group of diseases or disorders iprazole, or a pro-drug or an active metabolite thereof, or a consisting of mood disorders, anxiety disorders, psychotic pharmaceutically acceptable salt thereof. Even more prefer disorders, Somatoform disorders (excluding pain disorders), ably, said serotonin/dopamine antagonist compound is cho factitious disorders, dissociative disorders, sleep disorders, sen from the group consisting of SL 91.0177, , adjustment disorders, impulse control disorders, pervasive , , blonanserin, bifeprunoX and development disorders, disruptive behaviour disorders, sub asenapine, or a pro-drug or an active metabolite thereof, or a stance-related disorders, personality disorders, psychological pharmaceutically acceptable salt thereof. More preferably, factors affecting medical conditions, malingering, antisocial said serotonin/dopamine antagonist compound is sertindole behaviour, bereavement, occupational problem, identity 10 and is to be administered in a daily dose ranging between 12 problem, problems related to abuse or neglect, pain disorders and 24 mg of the active ingredient. More preferably, said and delirium. serotonin/dopamine antagonist compound is paliperidone The present invention thus relates to the use of pipamperon and is to be administered in a daily dose ranging between 3 or a pharmaceutically acceptable salt thereof for the prepara and 15 mg of the active ingredient. More preferably, said tion of a medicament for treating the underlying emotion 15 serotonin/dopamine antagonist compound is asenapine and is dysregulation of a non-cognitive mental disease or disorder to be administered in a daily dose ranging between 2.5 and 20 selected from the group of diseases and disorders consisting mg of the active ingredient. of mood disorders, anxiety disorders, psychotic disorders, The invention also relates to a pharmaceutical composition Somatoform disorders (excluding pain disorders), factitious comprising (a) pipamperon, and (b) a serotonin/dopamine disorders, dissociative disorders, sleep disorders, adjustment antagonist compound, preferably chosen from the group con disorders, impulse control disorders, pervasive development sisting of SL 91.0177, sertindole, perospirone, paliperidone, disorders, disruptive behaviour disorders, substance-related blonanserin, bifeprunoX and asenapine, or a pro-drug or an disorders, personality disorders, psychological factors affect active metabolite thereof, or a pharmaceutically acceptable ing medical conditions, malingering, antisocial behaviour, salt thereof, as a combined preparation for simultaneous, bereavement, occupational problem, identity problem and 25 separate or sequential use for treating the underlying emotion problems related to abuse or neglect, characterized in that dysregulation of a mental disease or disorder which is chosen pipamperon or said pharmaceutically acceptable salt thereof from the group consisting mood disorders, anxiety disorders, is administered simultaneously with, separate from or prior to psychotic disorders, somatoform disorders (excluding pain the administration of a serotonin/dopamine antagonist com disorders), factitious disorders, dissociative disorders, sleep pound to augment the therapeutic effect or to provide a faster 30 disorders, adjustment disorders, impulse control disorders, onset of the therapeutic effect of said serotonin/dopamine pervasive development disorders, disruptive behaviour disor antagonist compound, further characterized in that pipam ders, substance-related disorders, personality disorders, psy peron is to be administered to a patient in a daily dose ranging chological factors affecting medical conditions, malingering, between 5 and 15 mg of the active ingredient. antisocial behaviour, bereavement, occupational problem, The present invention thus relates to the use of pipamperon 35 identity problem, problems related to abuse or neglect, pain or a pharmaceutically acceptable salt thereof for the prepara disorders and delirium. tion of a medicament for treating the underlying emotion The invention also relates to a pharmaceutical composition dysregulation of pain disorders, characterized in that pipam as described above wherein pipamperon is provided in a peron or said pharmaceutically acceptable salt thereof is unitary dose of between 5 and 15 mg of the active ingredient administered simultaneously with, separate from or prior to 40 and wherein said serotonin/dopamine antagonist compound the administration of a serotonin/dopamine antagonist com issertindole, preferably provided in a unitary dose of between pound to augment the therapeutic effect or to provide a faster 12 and 24 mg of the active ingredient. onset of the therapeutic effect of said serotonin/dopamine The invention also relates to a pharmaceutical composition antagonist compound, further characterized in that pipam as described above wherein pipamperon is provided in a peron is to be administered to a patient in a daily dose ranging 45 unitary dose of between 5 and 15 mg of the active ingredient between 5 and 15 mg of the active ingredient. and wherein said serotonin/dopamine antagonist compound The present invention thus relates to the use of pipamperon is paliperidone, preferably provided in a unitary dose of or a pharmaceutically acceptable salt thereof for the prepara between 3 and 15 mg of the active ingredient. tion of a medicament for treating the underlying emotion The invention also relates to a pharmaceutical composition dysregulation of a cognitive mental disease or disorder which 50 as described above wherein pipamperon is provided in a is delirium, characterized in that pipamperon or said pharma unitary dose of between 5 and 15 mg of the active ingredient ceutically acceptable salt thereof is administered simulta and wherein said serotonin/dopamine antagonist compound neously with, separate from or prior to the administration of a is asenapine, preferably provided in a unitary dose of between serotonin/dopamine antagonist compound to augment the 2.5 and 20 mg of the active ingredient. therapeutic effect or to provide a faster onset of the therapeu 55 85: Combination Therapy with a Selective SDRI Compound tic effect of said serotonin/dopamine antagonist compound, The mental disorders which can be treated using com further characterized in that pipamperon is to be administered pounds having a high selective affinity for the 5-HT2A and to a patientina daily dose ranging between 5 and 15 mg of the D4 receptor, for instance pipamperon, in a combination active ingredient. therapy with a selective serotonin and dopamine re-uptake According to a preferred embodiment, the invention relates 60 inhibitor (SDRI) compound, are chosen from the group of to the uses as described above, wherein said serotonin/ diseases or disorders consisting of mood disorders, anxiety dopamine antagonist compound is chosen from the group disorders, eating disorders, premenstrual syndrome, Somato consisting of , , SM-13496, SL 91.0177. form disorders (excluding pain disorders), factitious disor sertindole, S-18327, risperidone, quetiapine fumarate (pref ders, dissociative disorders, sleep disorders, adjustment dis erably Sustained release formulation), quetiapine fumarate 65 orders, impulse control disorders, Substance-related (preferably granules), quetiapine, peroSpirone, paliperidone, disorders, personality disorders, antisocial behaviour, , , LU 31-131, illoperidone, clozapine, bereavement, occupational problem, problems related to US 8,304,431 B2 101 102 abuse or neglect, pain disorders, delirium, Alzheimer Dis nin and dopamine reuptake inhibitor (SDRI) compound is ease, Substance-induced persisting dementia, Vascular baZinaprine, or a pro-drug or an active metabolite thereof, or dementia, dementia due to HIV disease, dementia due to head a pharmaceutically acceptable salt thereof. trauma, dementia due to Parkinson Disease, dementia due to The invention also relates to a pharmaceutical composition Huntington Disease, dementia due to Pick Disease, dementia comprising (a) pipamperon, and (b) a selective serotonin and due to Creutzfeldt-Jacob Disease, amnestic disorders due to a dopamine reuptake inhibitor (SDRI) compound, preferably general medical condition, Substance-induced persisting baZinaprine or a pro-drug oran active metabolite thereof, or a amnestic disorder, mild cognitive impairment disorder and pharmaceutically acceptable salt thereof, as a combined other cognitive disorders. preparation for simultaneous, separate or sequential use for The present invention thus relates to the use of pipamperon 10 treating the underlying emotion dysregulation of mental dis or a pharmaceutically acceptable salt thereof for the prepara ease or disorder which is chosen from the group consisting of tion of a medicament for treating the underlying emotion mood disorders, anxiety disorders, eating disorders, premen dysregulation of a non-cognitive mental disease or disorder strual syndrome, Somatoform disorders (excluding pain dis selected from the group of diseases and disorders consisting orders), factitious disorders, dissociative disorders, sleep dis of mood disorders, anxiety disorders, eating disorders, pre 15 orders, adjustment disorders, impulse control disorders, menstrual syndrome, Somatoform disorders (excluding pain Substance-related disorders, personality disorders, antisocial disorders), factitious disorders, dissociative disorders, sleep behaviour, bereavement, occupational problem, problems disorders, adjustment disorders, impulse control disorders, related to abuse or neglect, pain disorders, delirium, Alzhe Substance-related disorders, personality disorders, antisocial imer Disease, Substance-induced persisting dementia, Vascu behaviour, bereavement, occupational problem and problems lar dementia, dementia due to HIV disease, dementia due to related to abuse or neglect, characterized in that pipamperon head trauma, dementia due to Parkinson Disease, dementia or said pharmaceutically acceptable salt thereof is adminis due to Huntington Disease, dementia due to Pick Disease, tered simultaneously with, separate from or prior to the dementia due to Creutzfeldt-Jacob Disease, amnestic disor administration of a selective serotonin and dopamine ders due to a general medical condition, Substance-induced reuptake inhibitor (SDRI) compound to augment the thera 25 persisting amnestic disorder, mild cognitive impairment dis peutic effect or to provide a faster onset of the therapeutic order and other cognitive disorders. effect of said selective serotonin and dopamine reuptake 86: Combination Therapy with a Second Messenger Beta inhibitor (SDRI) compound, further characterized in that Agonist Compound pipamperon is to be administered to a patient in a daily dose The mental disorders which can be treated using com ranging between 5 and 15 mg of the active ingredient. 30 pounds having a high selective affinity for the 5-HT2A and The present invention thus relates to the use of pipamperon D4 receptor, for instance pipamperon, in a combination or a pharmaceutically acceptable salt thereof for the prepara therapy with a second messenger beta agonist compound, are tion of a medicament for treating the underlying emotion chosen from the group of diseases or disorders consisting of dysregulation of pain disorders, characterized in that pipam mood disorders, anxiety disorders, eating disorders, premen peron or said pharmaceutically acceptable salt thereof is 35 strual syndrome, Somatoform disorders (excluding pain dis administered simultaneously with, separate from or prior to orders), factitious disorders, dissociative disorders, sexual the administration of a selective serotonin and dopamine and gender identity disorders, sleep disorders, adjustment reuptake inhibitor (SDRI) compound to augment the thera disorders, impulse control disorders, personality disorders, peutic effect or to provide a faster onset of the therapeutic bereavement, occupational problem, problems related to effect of said selective serotonin and dopamine reuptake 40 abuse or neglect and pain disorders. inhibitor (SDRI) compound, further characterized in that The present invention thus relates to the use of pipamperon pipamperon is to be administered to a patient in a daily dose or a pharmaceutically acceptable salt thereof for the prepara ranging between 5 and 15 mg of the active ingredient. tion of a medicament for treating the underlying emotion The present invention thus relates to the use of pipamperon dysregulation of a non-cognitive mental disease or disorder or a pharmaceutically acceptable salt thereof for the prepara 45 selected from the group of diseases and disorders consisting tion of a medicament for treating the underlying emotion of mood disorders, anxiety disorders, eating disorders, pre dysregulation of a cognitive mental disease or disorder menstrual syndrome, Somatoform disorders (excluding pain selected from the group of diseases and disorders consisting disorders), factitious disorders, dissociative disorders, sexual of delirium, Alzheimer Disease, Substance-induced persist and gender identity disorders, sleep disorders, adjustment ing dementia, Vascular dementia, dementia due to HIV dis 50 disorders, impulse control disorders, personality disorders, ease, dementia due to head trauma, dementia due to Parkinson bereavement, occupational problem and problems related to Disease, dementia due to Huntington Disease, dementia due abuse or neglect, characterized in that pipamperon or said to Pick Disease, dementia due to Creutzfeldt-Jacob Disease, pharmaceutically acceptable salt thereof is administered amnestic disorders due to a general medical condition, Sub simultaneously with, separate from or prior to the adminis stance-induced persisting amnestic disorder, mild cognitive 55 tration of a second messenger beta agonist compound to impairment disorder and other cognitive disorders, character augment the therapeutic effect or to provide a faster onset of ized in that pipamperon or said pharmaceutically acceptable the therapeutic effect of said second messenger beta agonist salt thereof is administered simultaneously with, separate compound, further characterized in that pipamperon is to be from or prior to the administration of a selective serotonin and administered to a patient in a daily dose ranging between 5 dopamine reuptake inhibitor (SDRI) compound to augment 60 and 15 mg of the active ingredient. the therapeutic effect or to provide a faster onset of the thera The present invention thus relates to the use of pipamperon peutic effect of said selective serotonin and dopamine or a pharmaceutically acceptable salt thereof for the prepara reuptake inhibitor (SDRI) compound, further characterized tion of a medicament for treating the underlying emotion in that pipamperon is to be administered to a patient in a daily dysregulation of pain disorders, characterized in that pipam dose ranging between 5 and 15 mg of the active ingredient. 65 peron or said pharmaceutically acceptable salt thereof is According to a preferred embodiment, the invention relates administered simultaneously with, separate from or prior to to the uses as described above, wherein said selective seroto the administration of a second messenger beta agonist com US 8,304,431 B2 103 104 pound to augment the therapeutic effect or to provide a faster administration of a secretin pancreatic hormone to augment onset of the therapeutic effect of said second messenger beta the therapeutic effect or to provide a faster onset of the thera agonist compound, further characterized in that pipamperon peutic effect of said secretin pancreatic hormone, further is to be administered to a patient in a daily dose ranging characterized in that pipamperon is to be administered to a between 5 and 15 mg of the active ingredient. patient in a daily dose ranging between 5 and 15 mg of the According to a preferred embodiment, the invention relates active ingredient. to the uses as described above, wherein said second messen The present invention thus relates to the use of pipamperon ger beta agonist compound is chosen from the group consist or a pharmaceutically acceptable salt thereof for the prepara ing of SR 57227, rolipram and , or a pro-drug or tion of a medicament for treating the underlying emotion an active metabolite thereof, or a pharmaceutically accept 10 dysregulation of pain disorders, characterized in that pipam able salt thereof. More preferably, said second messenger peron or said pharmaceutically acceptable salt thereof is beta agonist compound is rolipram and is to be administered administered simultaneously with, separate from or prior to in a daily dose ranging between 1.5 and 3 mg of the active the administration of a secretin pancreatic hormone to aug ingredient. ment the therapeutic effect or to provide a faster onset of the The invention also relates to a pharmaceutical composition 15 therapeutic effect of said secretin pancreatic hormone, further comprising (a) pipamperon, and (b) a second messenger beta characterized in that pipamperon is to be administered to a agonist compound, preferably chosen from the group consist patient in a daily dose ranging between 5 and 15 mg of the ing of SR 57227, rolipram and eplivanserin or a pro-drug or active ingredient. an active metabolite thereof, or a pharmaceutically accept The present invention thus relates to the use of pipamperon able salt thereof, as a combined preparation for simultaneous, or a pharmaceutically acceptable salt thereof for the prepara separate or sequential use for treating the underlying emotion tion of a medicament for treating the underlying emotion dysregulation of a mental disease or disorder which is chosen dysregulation of a cognitive mental disease or disorder which from the group consisting of mood disorders, anxiety disor is delirium, characterized in that pipamperon or said pharma ders, eating disorders, premenstrual syndrome, Somatoform ceutically acceptable salt thereof is administered simulta disorders (excluding pain disorders), factitious disorders, dis 25 neously with, separate from or prior to the administration of a Sociative disorders, sexual and gender identity disorders, secretin pancreatic hormone to augment the therapeutic effect sleep disorders, adjustment disorders, impulse control disor or to provide a faster onset of the therapeutic effect of said ders, personality disorders, bereavement, occupational prob secretin pancreatic hormone, further characterized in that lem, problems related to abuse or neglect and pain disorders. pipamperon is to be administered to a patient in a daily dose The invention also relates to a pharmaceutical composition 30 ranging between 5 and 15 mg of the active ingredient. as described above wherein pipamperon is provided in a According to a preferred embodiment, the invention relates unitary dose of between 5 and 15 mg of the active ingredient to the uses as described above, wherein said secretin pancre and wherein said second messenger beta agonist compound is atic hormone is RG1068 or a pro-drug oran active metabolite rolipram, preferably provided in a unitary dose of between 1.5 thereof, or a pharmaceutically acceptable salt thereof. and 3 mg of the active ingredient. 35 The invention also relates to a pharmaceutical composition 87: Combination Therapy with a Secretin Pancreatic Hor comprising (a) pipamperon, and (b) a secretin pancreatic O hormone, preferably RG1068, or a pro-drug or an active The mental disorders which can be treated using com metabolite thereof, or a pharmaceutically acceptable salt pounds having a high selective affinity for the 5-HT2A and thereof, as a combined preparation for simultaneous, separate D4 receptor, for instance pipamperon, in a combination 40 or sequential use for treating the underlying emotion dysregu therapy with a secretin pancreatic hormone, are chosen from lation of amental disease or disorder which is chosen from the the group of diseases or disorders consisting of anxiety dis group consisting of anxiety disorders, psychotic disorders, orders, psychotic disorders, Somatoform disorders (exclud Somatoform disorders (excluding pain disorders), factitious ing pain disorders), factitious disorders, dissociative disor disorders, dissociative disorders, sleep disorders, adjustment ders, sleep disorders, adjustment disorders, impulse control 45 disorders, impulse control disorders, pervasive development disorders, pervasive development disorders, disruptive disorders, disruptive behaviour disorders, substance-related behaviour disorders, Substance-related disorders, personality disorders, personality disorders, psychological factors affect disorders, psychological factors affecting medical condi ing medical conditions, malingering, antisocial behaviour, tions, malingering, antisocial behaviour, bereavement, occu bereavement, occupational problem, identity problem, prob pational problem, identity problem, problems related to abuse 50 lems related to abuse or neglect, pain disorders and delirium. or neglect, pain disorders and delirium. 88: Combination Therapy with a Sigma Receptor Agonist The present invention thus relates to the use of pipamperon Compound or a pharmaceutically acceptable salt thereof for the prepara The mental disorders which can be treated using com tion of a medicament for treating the underlying emotion pounds having a high selective affinity for the 5-HT2A and dysregulation of a non-cognitive mental disease or disorder 55 D4 receptor, for instance pipamperon, in a combination selected from the group of diseases and disorders consisting therapy with a sigma receptoragonist compound, are chosen of anxiety disorders, psychotic disorders, somatoform disor from the group of diseases or disorders consisting of mood ders (excluding pain disorders), factitious disorders, disso disorders, anxiety disorders, eating disorders, premenstrual ciative disorders, sleep disorders, adjustment disorders, syndrome, Somatoform disorders (excluding pain disorders), impulse control disorders, pervasive development disorders, 60 factitious disorders, dissociative disorders, sexual and gender disruptive behaviour disorders, substance-related disorders, identity disorders, sleep disorders, adjustment disorders, personality disorders, psychological factors affecting medi impulse control disorders, attention-deficit disorders, person cal conditions, malingering, antisocial behaviour, bereave ality disorders, bereavement, occupational problem, prob ment, occupational problem, identity problem and problems lems related to abuse or neglect and pain disorders. related to abuse or neglect, characterized in that pipamperon 65 The present invention thus relates to the use of pipamperon or said pharmaceutically acceptable salt thereof is adminis or a pharmaceutically acceptable salt thereof for the prepara tered simultaneously with, separate from or prior to the tion of a medicament for treating the underlying emotion US 8,304,431 B2 105 106 dysregulation of a non-cognitive mental disease or disorder The present invention thus relates to the use of pipamperon selected from the group of diseases and disorders consisting or a pharmaceutically acceptable salt thereof for the prepara of mood disorders, anxiety disorders, eating disorders, pre tion of a medicament for treating the underlying emotion menstrual syndrome, Somatoform disorders (excluding pain dysregulation of a non-cognitive mental disease or disorder disorders), factitious disorders, dissociative disorders, sexual selected from the group of diseases and disorders consisting and gender identity disorders, sleep disorders, adjustment of mood disorders, anxiety disorders, psychotic disorders, disorders, impulse control disorders, attention-deficit disor eating disorders, premenstrual syndrome, Somatoform disor ders, personality disorders, bereavement, occupational prob ders (excluding pain disorders), factitious disorders, disso lem and problems related to abuse or neglect, characterized in ciative disorders, sexual and gender identity disorders, sleep that pipamperon or said pharmaceutically acceptable salt 10 disorders, adjustment disorders, impulse control disorders, thereof is administered simultaneously with, separate from or pervasive development disorders, disruptive behaviour disor prior to the administration of a sigma receptor agonist com ders, Substance-related disorders, personality disorders, pound to augment the therapeutic effect or to provide a faster bereavement, occupational problem and problems related to onset of the therapeutic effect of said Sigma receptor agonist abuse or neglect, characterized in that pipamperon or said compound, further characterized in that pipamperon is to be 15 pharmaceutically acceptable salt thereof is administered administered to a patient in a daily dose ranging between 5 simultaneously with, separate from or prior to the adminis and 15 mg of the active ingredient. tration of a sigma receptor antagonist compound to augment The present invention thus relates to the use of pipamperon the therapeutic effect or to provide a faster onset of the thera or a pharmaceutically acceptable salt thereof for the prepara peutic effect of said sigma receptor antagonist compound, tion of a medicament for treating the underlying emotion further characterized in that pipamperon is to be administered dysregulation of pain disorders, characterized in that pipam to a patientina daily dose ranging between 5 and 15 mg of the peron or said pharmaceutically acceptable salt thereof is active ingredient. administered simultaneously with, separate from or prior to The present invention thus relates to the use of pipamperon the administration of a sigma receptor agonist compound to or a pharmaceutically acceptable salt thereof for the prepara augment the therapeutic effect or to provide a faster onset of 25 tion of a medicament for treating the underlying emotion the therapeutic effect of said sigma receptor agonist com dysregulation of pain disorders, characterized in that pipam pound, further characterized in that pipamperon is to be peron or said pharmaceutically acceptable salt thereof is administered to a patient in a daily dose ranging between 5 administered simultaneously with, separate from or prior to and 15 mg of the active ingredient. the administration of a sigma receptor antagonist compound According to a preferred embodiment, the invention relates 30 to augment the therapeutic effect or to provide a faster onset to the uses as described above, wherein said sigma receptor of the therapeutic effect of said sigma receptor antagonist agonist compound is VPI-013 (also known as OPC-14523) or compound, further characterized in that pipamperon is to be PRX-00023, preferably VPI-013 (also known as OPC administered to a patient in a daily dose ranging between 5 14523), or a pro-drug or an active metabolite thereof, or a and 15 mg of the active ingredient. pharmaceutically acceptable salt thereof. 35 The present invention thus relates to the use of pipamperon The invention also relates to a pharmaceutical composition or a pharmaceutically acceptable salt thereof for the prepara comprising (a) pipamperon, and (b) a sigma receptoragonist tion of a medicament for treating the underlying emotion compound, preferably VPI-013 (also known as OPC-14523) dysregulation of a cognitive mental disease or disorder which or PRX-00023, preferably VPI-013 (also known as OPC is delirium, characterized in that pipamperon or said pharma 14523), or a pro-drug or an active metabolite thereof, or a 40 ceutically acceptable salt thereof is administered simulta pharmaceutically acceptable salt thereof, as a combined neously with, separate from or prior to the administration of a preparation for simultaneous, separate or sequential use for sigma receptor antagonist compound to augment the thera treating the underlying emotion dysregulation of a mental peutic effect or to provide a faster onset of the therapeutic disease or disorder which is chosen from the group consisting effect of said sigma receptor antagonist compound, further of mood disorders, anxiety disorders, eating disorders, pre 45 characterized in that pipamperon is to be administered to a menstrual syndrome, Somatoform disorders (excluding pain patient in a daily dose ranging between 5 and 15 mg of the disorders), factitious disorders, dissociative disorders, sexual active ingredient. and gender identity disorders, sleep disorders, adjustment According to a preferred embodiment, the invention relates disorders, impulse control disorders, attention-deficit disor to the uses as described above, wherein said sigma receptor ders, personality disorders, bereavement, occupational prob 50 antagonist compound is chosen from the group consisting of lem, problems related to abuse or neglect and pain disorders. SR31742 and EMD 68843, or a pro-drug oran active metabo 89: Combination Therapy with a Sigma Receptor Antagonist lite thereof, or a pharmaceutically acceptable salt thereof. Compound More preferably, said sigma receptor antagonist compound is The mental disorders which can be treated using com EMD 68843 and is to be administered in a daily dose ranging pounds having a high selective affinity for the 5-HT2A and 55 between 5 and 40 mg of the active ingredient. D4 receptor, for instance pipamperon, in a combination The invention also relates to a pharmaceutical composition therapy with a sigma receptor antagonist compound, are cho comprising (a) pipamperon, and (b) a sigma receptor antago Sen from the group of diseases or disorders consisting of nist compound, preferably chosen from the group consisting mood disorders, anxiety disorders, psychotic disorders, eat of SR 31742 and EMD 68843, or a pro-drug or an active ing disorders, premenstrual syndrome, Somatoform disorders 60 metabolite thereof, or a pharmaceutically acceptable salt (excluding pain disorders), factitious disorders, dissociative thereof, as a combined preparation for simultaneous, separate disorders, sexual and gender identity disorders, sleep disor or sequential use for treating the underlying emotion dysregu ders, adjustment disorders, impulse control disorders, perva lation of amental disease or disorder which is chosen from the sive development disorders, disruptive behaviour disorders, group consisting mood disorders, anxiety disorders, psy Substance-related disorders, personality disorders, bereave 65 chotic disorders, eating disorders, premenstrual syndrome, ment, occupational problem, problems related to abuse or Somatoform disorders (excluding pain disorders), factitious neglect, pain disorders and delirium. disorders, dissociative disorders, sexual and gender identity US 8,304,431 B2 107 108 disorders, sleep disorders, adjustment disorders, impulse further characterized in that pipamperon is to be administered control disorders, pervasive development disorders, disrup to a patientina daily dose ranging between 5 and 15 mg of the tive behaviour disorders, substance-related disorders, person active ingredient. ality disorders, bereavement, occupational problem, prob The present invention thus relates to the use of pipamperon lems related to abuse or neglect, pain disorders and delirium. or a pharmaceutically acceptable salt thereof for the prepara The invention also relates to a pharmaceutical composition tion of a medicament for treating the underlying emotion as described above wherein pipamperon is provided in a dysregulation of a cognitive mental disease or disorder unitary dose of between 5 and 15 mg of the active ingredient selected from the group of diseases and disorders consisting and wherein said sigma receptor antagonist compound is of delirium, Alzheimer Disease, Substance-induced persist EMD 68843, preferably provided in a unitary dose of 10 ing dementia, Vascular dementia, dementia due to HIV dis between 5 and 40 mg of the active ingredient. ease, dementia due to head trauma, dementia due to Parkinson 90: Combination Therapy with a Selective SNDRI Com Disease, dementia due to Huntington Disease, dementia due pound to Pick Disease, dementia due to Creutzfeldt-Jacob Disease, The mental disorders which can be treated using com amnestic disorders due to a general medical condition, Sub pounds having a high selective affinity for the 5-HT2A and 15 stance-induced persisting amnestic disorder, mild cognitive D4 receptor, for instance pipamperon, in a combination impairment disorder and other cognitive disorders, character therapy with a selective serotonin, nor-adrenaline and dopam ized in that pipamperon or said pharmaceutically acceptable ine re-uptake inhibitor (SNDRI) compound, are chosen from salt thereof is administered simultaneously with, separate the group of diseases or disorders consisting of mood disor from or prior to the administration of a selective serotonin, ders, anxiety disorders, eating disorders, premenstrual Syn nor-adrenaline and dopamine re-uptake inhibitor (SNDRI) drome. Somatoform disorders (excluding pain disorders), fac compound to augment the therapeutic effect or to provide a titious disorders, dissociative disorders, sleep disorders, faster onset of the therapeutic effect of said selective seroto adjustment disorders, impulse control disorders, attention nin, nor-adrenaline and dopamine re-uptake inhibitor (SN deficit disorders, Substance-related disorders, personality dis DRI) compound, further characterized in that pipamperon is orders, antisocial behaviour, bereavement, occupational 25 to be administered to a patient in a daily dose ranging between problem, problems related to abuse or neglect, pain disorders, 5 and 15 mg of the active ingredient. delirium, Alzheimer Disease, Substance-induced persisting According to a preferred embodiment, the invention relates dementia, Vascular dementia, dementia due to HIV disease, to the uses as described above, wherein said selective seroto dementia due to head trauma, dementia due to Parkinson nin, nor-adrenaline and dopamine re-uptake inhibitor (SN Disease, dementia due to Huntington Disease, dementia due 30 DRI) compound is selected from the group consisting of NS to Pick Disease, dementia due to Creutzfeldt-Jacob Disease, 2330; McN 5652: DOV 216,303 and DOV 21,947; more amnestic disorders due to a general medical condition, Sub preferably NS 2330 or DOV 216.303; or a pro-drug or an stance-induced persisting amnestic disorder, mild cognitive active metabolite thereof; or a pharmaceutically acceptable impairment disorder and other cognitive disorders. salt thereof. The present invention thus relates to the use of pipamperon 35 The invention also relates to a pharmaceutical composition or a pharmaceutically acceptable salt thereof for the prepara comprising (a) pipamperon, and (b) a selective serotonin, tion of a medicament for treating the underlying emotion nor-adrenaline and dopamine re-uptake inhibitor (SNDRI) dysregulation of a non-cognitive mental disease or disorder compound, preferably selected from the group consisting of selected from the group of diseases and disorders consisting NS 2330; McN 5652: DOV 216,303 and DOV 21,947, more of mood disorders, anxiety disorders, eating disorders, pre 40 preferably NS 2330 or DOV 216,303, or a pro-drug or an menstrual syndrome, Somatoform disorders (excluding pain active metabolite thereof, or a pharmaceutically acceptable disorders), factitious disorders, dissociative disorders, sleep salt thereof, as a combined preparation for simultaneous, disorders, adjustment disorders, impulse control disorders, separate or sequential use for treating the underlying emotion attention-deficit disorders, Substance-related disorders, per dysregulation of mental disease or disorder which is chosen Sonality disorders, antisocial behaviour, bereavement, occu 45 from the group consisting of mood disorders, anxiety disor pational problem and problems related to abuse or neglect, ders, eating disorders, premenstrual syndrome, Somatoform characterized in that pipamperon or said pharmaceutically disorders (excluding pain disorders), factitious disorders, dis acceptable salt thereof is administered simultaneously with, Sociative disorders, sleep disorders, adjustment disorders, separate from or prior to the administration of a selective impulse control disorders, attention-deficit disorders, Sub serotonin, nor-adrenaline and dopamine re-uptake inhibitor 50 stance-related disorders, personality disorders, antisocial (SNDRI) compound to augment the therapeutic effect or to behaviour, bereavement, occupational problem, problems provide a faster onset of the therapeutic effect of said selective related to abuse or neglect, pain disorders, delirium, Alzhe serotonin, nor-adrenaline and dopamine re-uptake inhibitor imer Disease, Substance-induced persisting dementia, Vascu (SNDRI) compound, further characterized in that pipam lar dementia, dementia due to HIV disease, dementia due to peron is to be administered to a patient in a daily dose ranging 55 head trauma, dementia due to Parkinson Disease, dementia between 5 and 15 mg of the active ingredient. due to Huntington Disease, dementia due to Pick Disease, The present invention thus relates to the use of pipamperon dementia due to Creutzfeldt-Jacob Disease, amnestic disor or a pharmaceutically acceptable salt thereof for the prepara ders due to a general medical condition, Substance-induced tion of a medicament for treating the underlying emotion persisting amnestic disorder, mild cognitive impairment dis dysregulation of pain disorders, characterized in that pipam 60 order and other cognitive disorders. peron or said pharmaceutically acceptable salt thereof is 91: Combination Therapy with a Selective SNRI Compound administered simultaneously with, separate from or prior to The mental disorders which can be treated using com the administration of a selective serotonin, nor-adrenaline pounds having a high selective affinity for the 5-HT2A and and dopamine re-uptake inhibitor (SNDRI) compound to D4 receptor, for instance pipamperon, in a combination augment the therapeutic effect or to provide a faster onset of 65 therapy with a selective serotonin and nor-adrenaline re-up the therapeutic effect of said seective serotonin, nor-adrena take inhibitor (SNRI) compound, are chosen from the group line and dopamine re-uptake inhibitor (SNDRI) compound, of diseases or disorders consisting of mood disorders, anxiety US 8,304,431 B2 109 110 disorders, eating disorders, premenstrual syndrome, Somato compound is dulloxetine and is to be administered in a daily form disorders (excluding pain disorders), factitious disor dose ranging between 40 and 60 mg of the active ingredient. ders, dissociative disorders, sleep disorders, adjustment dis The invention also relates to a pharmaceutical composition orders, impulse control disorders, attention-deficit disorders, comprising (a) pipamperon, and (b) a selective serotonin and Substance-related disorders, personality disorders, antisocial nor-adrenaline re-uptake inhibitor (SNRI) compound, pref behaviour, bereavement, occupational problem, problems erably selected from the group consisting of Venlafaxine, related to abuse or neglect and pain disorders. tomoxetine, tandamine, talsupram, talopram, , The present invention thus relates to the use of pipamperon milnacipran, LY 113.821, dulloxetine, desvenlafaxine and or a pharmaceutically acceptable salt thereof for the prepara , or a pro-drug or an active metabolite thereof, or a tion of a medicament for treating the underlying emotion 10 pharmaceutically acceptable salt thereof, as a combined dysregulation of a non-cognitive mental disease or disorder preparation for simultaneous, separate or sequential use for selected from the group of diseases and disorders consisting treating the underlying emotion dysregulation of mental dis of mood disorders, anxiety disorders, eating disorders, pre ease or disorder which is chosen from the group consisting of menstrual syndrome, Somatoform disorders (excluding pain mood disorders, anxiety disorders, eating disorders, premen disorders), factitious disorders, dissociative disorders, sleep 15 strual syndrome, Somatoform disorders (excluding pain dis disorders, adjustment disorders, impulse control disorders, orders), factitious disorders, dissociative disorders, sleep dis attention-deficit disorders, Substance-related disorders, per orders, adjustment disorders, impulse control disorders, Sonality disorders, antisocial behaviour, bereavement, occu attention-deficit disorders, Substance-related disorders, per pational problem and problems related to abuse or neglect, Sonality disorders, antisocial behaviour, bereavement, occu characterized in that pipamperon or said pharmaceutically pational problem, problems related to abuse or neglect and acceptable salt thereof is administered simultaneously with, pain disorders. separate from or prior to the administration of a selective The invention also relates to a pharmaceutical composition serotonin and nor-adrenaline re-uptake inhibitor (SNRI) as described above wherein pipamperon is provided in a compound to augment the therapeutic effect or to provide a unitary dose of between 5 and 15 mg of the active ingredient faster onset of the therapeutic effect of said selective seroto 25 and wherein said selective serotonin and nor-adrenaline re nin and nor-adrenaline re-uptake inhibitor (SNRI) com uptake inhibitor (SNRI) compound is venlafaxine, preferably pound, further characterized in that pipamperon is to be provided in a unitary dose of between 75 and 300 mg of the administered to a patient in a daily dose ranging between 5 active ingredient. and 15 mg of the active ingredient. The invention also relates to a pharmaceutical composition The present invention thus relates to the use of pipamperon 30 as described above wherein pipamperon is provided in a or a pharmaceutically acceptable salt thereof for the prepara unitary dose of between 5 and 15 mg of the active ingredient tion of a medicament for treating the underlying emotion and wherein said selective serotonin and nor-adrenaline re dysregulation of pain disorders, characterized in that pipam uptake inhibitor (SNRI) compound is tomoxetine, preferably peron or said pharmaceutically acceptable salt thereof is provided in a unitary dose of between 0.475 and 3.8 mg/kg of administered simultaneously with, separate from or prior to 35 the active ingredient. the administration of a selective serotonin and nor-adrenaline The invention also relates to a pharmaceutical composition re-uptake inhibitor (SNRI) compound to augment the thera as described above wherein pipamperon is provided in a peutic effect or to provide a faster onset of the therapeutic unitary dose of between 5 and 15 mg of the active ingredient effect of said selective serotonin and nor-adrenaline re-uptake and wherein said selective serotonin and nor-adrenaline re inhibitor (SNRI) compound, further characterized in that 40 uptake inhibitor (SNRI) compound is milnacipran, preferably pipamperon is to be administered to a patient in a daily dose provided in a unitary dose of between 50 and 200 mg of the ranging between 5 and 15 mg of the active ingredient. active ingredient. According to a preferred embodiment, the invention relates The invention also relates to a pharmaceutical composition to the uses as described above, wherein said selective seroto as described above wherein pipamperon is provided in a nin and nor-adrenaline re-uptake inhibitor (SNRI) compound 45 unitary dose of between 5 and 15 mg of the active ingredient is selected from the group consisting of Venlafaxine, tomox and wherein said selective serotonin and nor-adrenaline re etine, tandamine, talsupram, talopram, nefazodone, mil uptake inhibitor (SNRI) compound is duloxetine, preferably nacipran, LY 113.821, dulloxetine, desvenlafaxine and amox provided in a unitary dose of between 40 and 60 mg of the apine, or a pro-drug or an active metabolite thereof, or a active ingredient. pharmaceutically acceptable salt thereof. Even more prefer 50 92: Combination Therapy with a Selective Serotonin Re ably, said selective serotonin and nor-adrenaline re-uptake Uptake Inhibitor (SSRI) Compound inhibitor (SNRI) compound is chosen from the group con The mental disorders which can be treated using com sisting of Venlafaxine, tomoxetine, milnacipran, dulloxetine pounds having a high selective affinity for the 5-HT2A and and desvenlafaxine, or a pro-drug or an active metabolite D4 receptor, for instance pipamperon, in a combination thereof, or a pharmaceutically acceptable salt thereof. More 55 therapy with a selective serotonin re-uptake inhibitor (SSRI) preferably, said selective serotonin and nor-adrenaline re compound, are chosen from the group of diseases or disorders uptake inhibitor (SNRI) compound is venlafaxine and is to be consisting of mood disorders, anxiety disorders, eating dis administered in a daily dose ranging between 75 and 300 mg orders, premenstrual syndrome, Somatoform disorders (ex of the active ingredient. More preferably, said selective sero cluding pain disorders), factitious disorders, dissociative dis tonin and nor-adrenaline re-uptake inhibitor (SNRI) com 60 orders, sleep disorders, adjustment disorders, impulse control pound is tomoxetine and is to be administered in a daily dose disorders, Substance-related disorders, personality disorders, ranging between 0.475 and 3.8 mg/kg of the active ingredient. antisocial behaviour, bereavement, occupational problem, More preferably, said selective serotonin and nor-adrenaline problems related to abuse or neglect and pain disorders. re-uptake inhibitor (SNRI) compound is milnacipranand is to The present invention thus relates to the use of pipamperon be administered in a daily dose ranging between 50 and 200 65 or a pharmaceutically acceptable salt thereof for the prepara mg of the active ingredient. More preferably, said selective tion of a medicament for treating the underlying emotion serotonin and nor-adrenaline re-uptake inhibitor (SNRI) dysregulation of a non-cognitive mental disease or disorder US 8,304,431 B2 111 112 selected from the group of diseases and disorders consisting acceptable salt thereof, as a combined preparation for simul of mood disorders, anxiety disorders, eating disorders, pre taneous, separate or sequential use for treating the underlying menstrual syndrome, Somatoform disorders (excluding pain emotion dysregulation of mental disease or disorder which is disorders), factitious disorders, dissociative disorders, sleep chosen from the group consisting of mood disorders, anxiety disorders, adjustment disorders, impulse control disorders, disorders, eating disorders, premenstrual syndrome, Somato Substance-related disorders, personality disorders, antisocial form disorders (excluding pain disorders), factitious disor behaviour, bereavement, occupational problem and problems ders, dissociative disorders, sleep disorders, adjustment dis related to abuse or neglect, characterized in that pipamperon orders, impulse control disorders, Substance-related or said pharmaceutically acceptable salt thereof is adminis disorders, personality disorders, antisocial behaviour, tered simultaneously with, separate from or prior to the 10 bereavement, occupational problem, problems related to administration of a selective serotonin re-uptake inhibitor abuse or neglect and pain disorders. (SSRI) compound to augment the therapeutic effect or to The invention also relates to a pharmaceutical composition provide a faster onset of the therapeutic effect of said selective as described above wherein pipamperon is provided in a serotonin re-uptake inhibitor (SSRI) compound, further char unitary dose of between 5 and 15 mg of the active ingredient acterized in that pipamperon is to be administered to a patient 15 and wherein said selective serotonin re-uptake inhibitor in a daily dose ranging between 5 and 15 mg of the active (SSRI) compound is fluvoxamine (controlled release formu ingredient. lation), preferably provided in a unitary dose of between 100 The present invention thus relates to the use of pipamperon and 300 mg of the active ingredient. or a pharmaceutically acceptable salt thereof for the prepara The invention also relates to a pharmaceutical composition tion of a medicament for treating the underlying emotion as described above wherein pipamperon is provided in a dysregulation of pain disorders, characterized in that pipam unitary dose of between 5 and 15 mg of the active ingredient peron or said pharmaceutically acceptable salt thereof is and wherein said selective serotonin re-uptake inhibitor administered simultaneously with, separate from or prior to (SSRI) compound is escitalopram, preferably provided in a the administration of a selective serotonin re-uptake inhibitor unitary dose of between 10 and 20 mg of the active ingredient. (SSRI) compound to augment the therapeutic effect or to 25 The invention also relates to a pharmaceutical composition provide a faster onset of the therapeutic effect of said selective as described above wherein pipamperon is provided in a serotonin re-uptake inhibitor (SSRI) compound, further char unitary dose of between 5 and 15 mg of the active ingredient acterized in that pipamperon is to be administered to a patient and wherein said selective serotonin re-uptake inhibitor in a daily dose ranging between 5 and 15 mg of the active (SSRI) compound is citalopram, preferably provided in a ingredient. 30 unitary dose of between 10 and 40 mg of the active ingredient. According to a preferred embodiment, the invention relates Citalopram or citalopram hydrobromide is a selective sero to the uses as described above, wherein said selective seroto tonin (5-hydroxytryptamine/5-HT) re-uptake inhibitor nin re-uptake inhibitor (SSRI) compound is selected from the (SSRI) and is the conventional name given for the compound group consisting of YM 992, VPI-013 (also known as OPC of the formula (RS)-1-3-(dimethylamino)propyl-1-(p-fluo 14523), sertra line, paroxetine, LY214.281, LUAA 21-004, 35 rophenyl)-5-phthalancarbonitrile-hydro-bromide. According Lu 35-138, , ifoxetine, fluvoxamine (controlled to an embodiment, a daily doses of active ingredient of SSRI, release formulation), fluvoxamine, fluoxetine, femoxetine, preferably citalopram, ranges between 10 and 40 mg per day. escitalopram, EMD 68843, cyanodothepine, citalopram, cer Preferably, daily doses of active ingredient ranging between iclamine and ademethionine (preferably S-adenosylmethion 20 and 30 mg per day are administered. More preferably, a ine), or a pro-drug or an active metabolite thereof, or a phar 40 daily dose of 10, 15, 20, 25, 30, 35 or 40 mg per day is maceutically acceptable salt thereof. Even more preferably, administered. said selective serotonin re-uptake inhibitor (SSRI) compound Fluvoxamine or fluvoxamine maleate (luvox, fevarin) is a is chosen from the group consisting of litoxetine, fluvoxam selective serotonin (5-HT) re-uptake inhibitor (SSRI) belong ine (controlled release formulation), citalopram and escitalo ing to a new chemical series, the 2-aminoethyl oxime ethers pram, or a pro-drug or an active metabolite thereof, or a 45 of aralkylketones. It is chemically unrelated to other SSRIs pharmaceutically acceptable salt thereof. More preferably, and clomipramine. It is chemically designated as 5-methoxy said selective serotonin re-uptake inhibitor (SSRI) compound 4'-(trifluoromethyl)Valerophenone (E)-O-(2-aminoethyl) is fluvoxamine (controlled release formulation) and is to be Oxime maleate (1:1). administered in a daily dose ranging between 100 and 300 mg According to an embodiment, a daily dose of active ingre of the active ingredient. More preferably, said selective sero 50 dient of fluvoxamine in a controlled release mode ranges tonin re-uptake inhibitor (SSRI) compound is escitalopram between 100 and 300 mg per day. Preferably, daily doses of and is to be administered in a daily dose ranging between 10 active ingredient ranging between 150 and 200 mg per day are and 20 mg of the active ingredient. More preferably, said administered in a controlled release mode. More preferably, a selective serotonin re-uptake inhibitor (SSRI) compound is daily dose of 100, 150, 200, 250 or 300 mg per day is admin citalopram and is to be administered in a daily dose ranging 55 istered by controlled release. between 10 and 40 mg of the active ingredient. 93: Combination Therapy with a Substance P Receptor The invention also relates to a pharmaceutical composition (NK1) Antagonist Compound comprising (a) pipamperon, and (b) a selective serotonin The mental disorders which can be treated using com re-uptake inhibitor (SSRI) compound, preferably selected pounds having a high selective affinity for the 5-HT2A and from the group consisting of YM 992, VPI-013 (also known 60 D4 receptor, for instance pipamperon, in a combination as OPC-14523), sertraline, paroxetine, LY214.281, LUAA therapy with a substance P receptor (NK1) antagonist com 21-004, Lu 35-138, litoxetine, ifoxetine, fluvoxamine (con pound, are chosen from the group of diseases or disorders trolled release formulation), fluvoxamine, fluoxetine, femo consisting of mood disorders, anxiety disorders, eating dis xetine, escitalopram, EMD 68843, cyanodothepine, citalo orders, premenstrual syndrome, Somatoform disorders (ex pram, Venlafaxine, milnacipran, dulloxetine, cericlamine and 65 cluding pain disorders), factitious disorders, dissociative dis ademethionine (preferably S-adenosylmethionine), or a pro orders, sexual and gender identity disorders, sleep disorders, drug or an active metabolite thereof, or a pharmaceutically adjustment disorders, impulse control disorders, Substance US 8,304,431 B2 113 114 related disorders, personality disorders, bereavement, occu and wherein said substance Preceptor (NK1) antagonist com pational problem, problems related to abuse or neglect and pound is aprepitant, preferably provided in a unitary dose of pain disorders. between 40 and 160 mg of the active ingredient. The present invention thus relates to the use of pipamperon 94: Combination Therapy with a Sulfonamide Compound or a pharmaceutically acceptable salt thereof for the prepara The mental disorders which can be treated using com tion of a medicament for treating the underlying emotion pounds having a high selective affinity for the 5-HT2A and dysregulation of a non-cognitive mental disease or disorder D4 receptor, for instance pipamperon, in a combination selected from the group of diseases and disorders consisting therapy with a sulfonamide compound, are chosen from the of mood disorders, anxiety disorders, eating disorders, pre group of diseases or disorders consisting of mood disorders, menstrual syndrome, Somatoform disorders (excluding pain 10 psychotic disorders, somatoform disorders (excluding pain disorders), factitious disorders, dissociative disorders, sexual disorders), factitious disorders, dissociative disorders, sleep and gender identity disorders, sleep disorders, adjustment disorders, adjustment disorders, impulse control disorders, disorders, impulse control disorders, Substance-related disor pervasive development disorders, disruptive behaviour disor ders, personality disorders, bereavement, occupational prob ders, Substance-related disorders, personality disorders, psy lem and problems related to abuse or neglect, characterized in 15 chological factors affecting medical conditions, malingering, that pipamperon or said pharmaceutically acceptable salt antisocial behaviour, bereavement, occupational problem, thereof is administered simultaneously with, separate from or identity problem, problems related to abuse or neglect, pain prior to the administration of a substance P receptor (NK1) disorders and delirium. antagonist compound to augment the therapeutic effect or to The present invention thus relates to the use of pipamperon provide a faster onset of the therapeutic effect of said sub or a pharmaceutically acceptable salt thereof for the prepara stance Preceptor (NK1) antagonist compound, further char tion of a medicament for treating the underlying emotion acterized in that pipamperon is to be administered to a patient dysregulation of a non-cognitive mental disease or disorder in a daily dose ranging between 5 and 15 mg of the active selected from the group of diseases and disorders consisting ingredient. of mood disorders, psychotic disorders, Somatoform disor The present invention thus relates to the use of pipamperon 25 ders (excluding pain disorders), factitious disorders, disso or a pharmaceutically acceptable salt thereof for the prepara ciative disorders, sleep disorders, adjustment disorders, tion of a medicament for treating the underlying emotion impulse control disorders, pervasive development disorders, dysregulation of pain, characterized in that pipamperon or disruptive behaviour disorders, substance-related disorders, said pharmaceutically acceptable salt thereof is administered personality disorders, psychological factors affecting medi simultaneously with, separate from or prior to the adminis 30 cal conditions, malingering, antisocial behaviour, bereave tration of a Substance Preceptor (NK1) antagonist compound ment, occupational problem, identity problem and problems to augment the therapeutic effect or to provide a faster onset related to abuse or neglect, characterized in that pipamperon of the therapeutic effect of said substance P receptor (NK1) or said pharmaceutically acceptable salt thereof is adminis antagonist compound, further characterized in that pipam tered simultaneously with, separate from or prior to the peron is to be administered to a patient in a daily dose ranging 35 administration of a Sulfonamide compound to augment the between 5 and 15 mg of the active ingredient. therapeutic effect or to provide a faster onset of the therapeu According to a preferred embodiment, the invention relates tic effect of said sulfonamide compound, further character to the uses as described above, wherein said substance P ized in that pipamperon is to be administered to a patient in a receptor (NK1) antagonist compound is chosen from the daily dose ranging between 5 and 15 mg of the active ingre group consisting of vestipitant, TAK-637, 8673, GW823296, 40 dient. GW679769, GW5975.99, CP-122.721, aprepitant, 823296 The present invention thus relates to the use of pipamperon and 679769, or a pro-drug or an active metabolite thereof, or or a pharmaceutically acceptable salt thereof for the prepara a pharmaceutically acceptable salt thereof. More preferably, tion of a medicament for treating the underlying emotion said Substance P receptor (NK1) antagonist compound is dysregulation of pain disorders, characterized in that pipam aprepitant and is to be administered in a daily dose ranging 45 peron or said pharmaceutically acceptable salt thereof is between 40 and 160 mg of the active ingredient. administered simultaneously with, separate from or prior to The invention also relates to a pharmaceutical composition the administration of a Sulfonamide compound to augment comprising (a) pipamperon, and (b) a Substance P receptor the therapeutic effect or to provide a faster onset of the thera (NK1) antagonist compound, preferably chosen from the peutic effect of said Sulfonamide compound, further charac group consisting of vestipitant, TAK-637, R673, GW823296, 50 terized in that pipamperon is to be administered to a patient in GW679769, GW5975.99, CP-122.721, aprepitant, 823296 a daily dose ranging between 5 and 15 mg of the active and 679769, or a pro-drug or an active metabolite thereof, or ingredient. a pharmaceutically acceptable salt thereof, as a combined The present invention thus relates to the use of pipamperon preparation for simultaneous, separate or sequential use for or a pharmaceutically acceptable salt thereof for the prepara treating the underlying emotion dysregulation of a mental 55 tion of a medicament for treating the underlying emotion disease or disorder which is chosen from the group of diseases dysregulation of a cognitive mental disease or disorder which and disorders consisting of mood disorders, anxiety disor is delirium, characterized in that pipamperon or said pharma ders, eating disorders, premenstrual syndrome, Somatoform ceutically acceptable salt thereof is administered simulta disorders (excluding pain disorders), factitious disorders, dis neously with, separate from or prior to the administration of a Sociative disorders, sexual and gender identity disorders, 60 Sulfonamide compound to augment the therapeutic effect or sleep disorders, adjustment disorders, impulse control disor to provide a faster onset of the therapeutic effect of said ders, Substance-related disorders, personality disorders, Sulfonamide compound, further characterized in that pipam bereavement, occupational problem, problems related to peron is to be administered to a patient in a daily dose ranging abuse or neglect and pain disorders. between 5 and 15 mg of the active ingredient. The invention also relates to a pharmaceutical composition 65 According to a preferred embodiment, the invention relates as described above wherein pipamperon is provided in a to the uses as described above, wherein said sulfonamide unitary dose of between 5 and 15 mg of the active ingredient compound is Zonisamide or a pro-drug oran active metabolite US 8,304,431 B2 115 116 thereof, or a pharmaceutically acceptable salt thereof. More augment the therapeutic effect or to provide a faster onset of preferably, said Sulfonamide compound is Zonisamide and is the therapeutic effect of said tachykinin antagonist com to be administered in a daily dose ranging between 100 and pound, further characterized in that pipamperon is to be 600 mg of the active ingredient. administered to a patient in a daily dose ranging between 5 The invention also relates to a pharmaceutical composition and 15 mg of the active ingredient. comprising (a) pipamperon, and (b) a Sulfonamide com According to a preferred embodiment, the invention relates pound, preferably Zonisamide, or a pro-drug or an active to the use as described above, wherein said tachykininantago metabolite thereof, or a pharmaceutically acceptable salt nist compound is SR 48968 or a pro-drug oran active metabo thereof, as a combined preparation for simultaneous, separate lite thereof, or a pharmaceutically acceptable salt thereof. or sequential use for treating the underlying emotion dysregu 10 The invention also relates to a pharmaceutical composition lation of amental disease or disorder which is chosen from the comprising (a) pipamperon, and (b) a tachykinin antagonist group consisting mood disorders, psychotic disorders, compound, preferably SR 48968 or a pro-drug or an active Somatoform disorders (excluding pain disorders), factitious metabolite thereof, or a pharmaceutically acceptable salt disorders, dissociative disorders, sleep disorders, adjustment thereof, as a combined preparation for simultaneous, separate disorders, impulse control disorders, pervasive development 15 or sequential use for treating the underlying emotion dysregu disorders, disruptive behaviour disorders, substance-related lation of amental disease or disorder which is chosen from the disorders, personality disorders, psychological factors affect group consisting of mood disorders, anxiety disorders, eating ing medical conditions, malingering, antisocial behaviour, disorders, premenstrual syndrome, Somatoform disorders bereavement, occupational problem, identity problem, prob (excluding pain disorders), factitious disorders, dissociative lems related to abuse or neglect, pain disorders and delirium. disorders, sexual and gender identity disorders, sleep disor The invention also relates to a pharmaceutical composition ders, adjustment disorders, impulse control disorders, Sub as described above wherein pipamperon is provided in a stance-related disorders, personality disorders, bereavement, unitary dose of between 5 and 15 mg of the active ingredient occupational problem, problems related to abuse or neglect and wherein said Sulfonamide compound is Zonisamide, pref and pain disorders. erably provided in a unitary dose of between 100 and 600 mg 25 96: Combination Therapy with a Compound Selected from of the active ingredient. the Group Consisting of R228060 (YKP-10A), Palanpanel, 95: Combination Therapy with a Tachykinin Antagonist ORG39479/PH80, ORG 34167, DP 543 and CJ-017.493 Compound The mental disorders which can be treated using com The mental disorders which can be treated using com pounds having a high selective affinity for the 5-HT2A and pounds having a high selective affinity for the 5-HT2A and 30 D4 receptor, for instance pipamperon, in a combination D4 receptor, for instance pipamperon, in a combination therapy with a compound selected from the group consisting therapy with a tachykinin antagonist compound, are chosen of R228060 (YKP-10A), palanpanel, ORG 39479/PH80, from the group of diseases or disorders consisting of mood ORG 34167, DP 543 and CJ-017.493, are chosen from the disorders, anxiety disorders, eating disorders, premenstrual group of diseases or disorders consisting of mood disorders, syndrome, Somatoform disorders (excluding pain disorders), 35 anxiety disorders, psychotic disorders, eating disorders, pre factitious disorders, dissociative disorders, sexual and gender menstrual syndrome, Somatoform disorders (excluding pain identity disorders, sleep disorders, adjustment disorders, disorders), factitious disorders, dissociative disorders, sexual impulse control disorders, Substance-related disorders, per and gender identity disorders, sleep disorders, adjustment Sonality disorders, bereavement, occupational problem, disorders, impulse control disorders, pervasive development problems related to abuse or neglect and pain disorders. 40 disorders, attention-deficit disorders, disruptive behaviour The present invention thus relates to the use of pipamperon disorders, Substance-related disorders, personality disorders, or a pharmaceutically acceptable salt thereof for the prepara psychological factors affecting medical conditions, malinger tion of a medicament for treating the underlying emotion ing, antisocial behaviour, bereavement, occupational prob dysregulation of a non-cognitive mental disease or disorder lem, identity problem, phase of life problem, academic prob selected from the group of diseases and disorders consisting 45 lem, problems related to abuse or neglect, pain disorders, of mood disorders, anxiety disorders, eating disorders, pre delirium, Alzheimer Disease, Substance-induced persisting menstrual syndrome, Somatoform disorders (excluding pain dementia, Vascular dementia, dementia due to REV disease, disorders), factitious disorders, dissociative disorders, sexual dementia due to head trauma, dementia due to Parkinson and gender identity disorders, sleep disorders, adjustment Disease, dementia due to Huntington Disease, dementia due disorders, impulse control disorders, Substance-related disor 50 to Pick Disease, dementia due to Creutzfeldt-Jacob Disease, ders, personality disorders, bereavement, occupational prob amnestic disorders due to a general medical condition, Sub lem and problems related to abuse or neglect, characterized in stance-induced persisting amnestic disorder, mild cognitive that pipamperon or said pharmaceutically acceptable salt impairment disorder, other cognitive disorders and Parkinson thereof is administered simultaneously with, separate from or Disease. prior to the administration of a tachykinin antagonist com 55 The present invention thus relates to the use of pipamperon pound to augment the therapeutic effect or to provide a faster or a pharmaceutically acceptable salt thereof for the prepara onset of the therapeutic effect of said tachykinin antagonist tion of a medicament for treating the underlying emotion compound, further characterized in that pipamperon is to be dysregulation of a non-cognitive mental disease or disorder administered to a patient in a daily dose ranging between 5 selected from the group of diseases and disorders consisting and 15 mg of the active ingredient. 60 of mood disorders, anxiety disorders, psychotic disorders, The present invention thus relates to the use of pipamperon eating disorders, premenstrual syndrome, Somatoform disor or a pharmaceutically acceptable salt thereof for the prepara ders (excluding pain disorders), factitious disorders, disso tion of a medicament for treating the underlying emotion ciative disorders, sexual and gender identity disorders, sleep dysregulation of pain disorders, characterized in that pipam disorders, adjustment disorders, impulse control disorders, peron or said pharmaceutically acceptable salt thereof is 65 pervasive development disorders, attention-deficit disorders, administered simultaneously with, separate from or prior to disruptive behaviour disorders, substance-related disorders, the administration of a tachykinin antagonist compound to personality disorders, psychological factors affecting medi US 8,304,431 B2 117 118 cal conditions, malingering, antisocial behaviour, bereave ORG 34167, DP543 and CJ-017.493, further characterized in ment, occupational problem, identity problem, phase of life that pipamperon is to be administered to a patient in a daily problem, academic problem and problems related to abuse or dose ranging between 5 and 15 mg of the active ingredient. neglect, characterized in that pipamperon or said pharmaceu The invention also relates to a pharmaceutical composition tically acceptable salt thereof is administered simultaneously comprising (a) pipamperon, and (b) a compound selected with, separate from or prior to the administration of a com from the group consisting of R228060 (YKP-10A), palan pound selected from the group consisting of R228060 (YKP panel, ORG 39479/PH80, ORG 34167, DP 543 and 10A), palanpanel, ORG 39479/PH80, ORG 34167, DP 543 CJ-017.493, or a pro-drug or an active metabolite thereof, or and CJ-017.493, to augment the therapeutic effect or to pro a pharmaceutically acceptable salt thereof, as a combined vide a faster onset of the therapeutic effect of said compound 10 selected from the group consisting of R228060 (YKP-10A), preparation for simultaneous, separate or sequential use for palanpanel, ORG 39479/PH80, ORG 34167, DP 543 and treating the underlying emotion dysregulation of mental dis CJ-017.493, further characterized in that pipamperon is to be ease or disorder which is chosen from the group consisting of administered to a patient in a daily dose ranging between 5 mood disorders, anxiety disorders, psychotic disorders, eat and 15 mg of the active ingredient. 15 ing disorders, premenstrual syndrome, somatoform disorders The present invention thus relates to the use of pipamperon (excluding pain disorders), factitious disorders, dissociative or a pharmaceutically acceptable salt thereof for the prepara disorders, sexual and gender identity disorders, sleep disor tion of a medicament for treating the underlying emotion ders, adjustment disorders, impulse control disorders, perva dysregulation of pain disorders, characterized in that pipam sive development disorders, attention-deficit disorders, dis peron or said pharmaceutically acceptable salt thereof is ruptive behaviour disorders, substance-related disorders, administered simultaneously with, separate from or prior to personality disorders, psychological factors affecting medi the administration of a compound selected from the group cal conditions, malingering, antisocial behaviour, bereave consisting of R228060 (YKP-10A), palanpanel, ORG39479/ ment, occupational problem, identity problem, phase of life PH80, ORG 34167, DP 543 and CJ-017.493, to augment the problem, academic problem, problems related to abuse or therapeutic effect or to provide a faster onset of the therapeu 25 neglect, pain disorders, delirium, Alzheimer Disease, Sub tic effect of said compound selected from the group consist stance-induced persisting dementia, vascular dementia, ing of R228060 (YKP-10A), palanpanel, ORG39479/PH80, dementia due to HIV disease, dementia due to head trauma, ORG 34167, DP543 and CJ-017.493, further characterized in dementia due to Parkinson Disease, dementia due to Hunting that pipamperon is to be administered to a patient in a daily ton Disease, dementia due to Pick Disease, dementia due to dose ranging between 5 and 15 mg of the active ingredient. 30 The present invention thus relates to the use of pipamperon Creutzfeldt-Jacob Disease, amnestic disorders due to a gen or a pharmaceutically acceptable salt thereof for the prepara eral medical condition, substance-induced persisting amnes tion of a medicament for treating the underlying emotion tic disorder, mild cognitive impairment disorder, other cog dysregulation of a non-cognitive mental disease or disorder nitive disorders and Parkinson Disease. selected from the group of diseases and disorders consisting 35 97: Combination Therapy with a Vasopressin 1B Receptor of delirium, Alzheimer Disease, Substance-induced persist (V1B) Antagonist Compound ing dementia, Vascular dementia, dementia due to HIV dis The mental disorders which can be treated using com ease, dementia due to head trauma, dementia due to Parkinson pounds having a high selective affinity for the 5-HT2A and Disease, dementia due to Huntington Disease, dementia due D4 receptor, for instance pipamperon, in a combination to Pick Disease, dementia due to Creutzfeldt-Jacob Disease, 40 therapy with a vasopressin 1B receptor (V1B) antagonist amnestic disorders due to a general medical condition, Sub compound, are chosen from the group of diseases or disorders stance-induced persisting amnestic disorder, mild cognitive consisting of mood disorders, anxiety disorders, eating dis impairment disorder and other cognitive disorders, character orders, premenstrual syndrome, Somatoform disorders (ex ized in that pipamperon or said pharmaceutically acceptable cluding pain disorders), factitious disorders, dissociative dis salt thereof is administered simultaneously with, separate 45 orders, sexual and gender identity disorders, sleep disorders, from or prior to the administration of a compound selected adjustment disorders, impulse control disorders, Substance from the group consisting of R228060 (YKP-10A), palan related disorders, personality disorders, bereavement, occu panel, ORG 39479/PH80, ORG 34167, DP 543 and pational problem, problems related to abuse or neglect and CJ-017.493, to augment the therapeutic effect or to provide a pain disorders. faster onset of the therapeutic effect of said compound 50 The present invention thus relates to the use of pipamperon selected from the group consisting of R228060 (YKP-10A), or a pharmaceutically acceptable salt thereof for the prepara palanpanel, ORG 39479/PH80, ORG 34167, DP 543 and tion of a medicament for treating the underlying emotion CJ-017.493, further characterized in that pipamperon is to be dysregulation of a non-cognitive mental disease or disorder administered to a patient in a daily dose ranging between 5 selected from the group of diseases and disorders consisting and 15 mg of the active ingredient. 55 of mood disorders, anxiety disorders, eating disorders, pre The present invention thus relates to the use of pipamperon menstrual syndrome, Somatoform disorders (excluding pain or a pharmaceutically acceptable salt thereof for the prepara disorders), factitious disorders, dissociative disorders, sexual tion of a medicament for treating the underlying emotion and gender identity disorders, sleep disorders, adjustment dysregulation of Parkinson Disease, characterized in that disorders, impulse control disorders, Substance-related disor pipamperon or said pharmaceutically acceptable salt thereof 60 ders, personality disorders, bereavement, occupational prob is administered simultaneously with, separate from or prior to lemand problems related to abuse or neglect, characterized in the administration of a compound selected from the group that pipamperon or said pharmaceutically acceptable salt consisting of R228060 (YKP-10A), palanpanel, ORG39479/ thereof is administered simultaneously with, separate from or PH80, ORG 34167, DP 543 and CJ-017.493, to augment the prior to the administration of a vasopressin 1B receptor (V1B) therapeutic effect or to provide a faster onset of the therapeu 65 antagonist compound to augment the therapeutic effect or to tic effect of said compound selected from the group consist provide a faster onset of the therapeutic effect of said vaso ing of R228060 (YKP-10A), palanpanel, ORG39479/PH80, pressin 1B receptor (V1B) antagonist compound, further US 8,304,431 B2 119 120 characterized in that pipamperon is to be administered to a therapeutic effect or to provide a faster onset of the therapeu patient in a daily dose ranging between 5 and 15 mg of the tic effect of said Voltage-gated calcium channel alpha(2)delta active ingredient. Subunit modulator compound, further characterized in that The present invention thus relates to the use of pipamperon pipamperon is to be administered to a patient in a daily dose or a pharmaceutically acceptable salt thereof for the prepara- 5 ranging between 5 and 15 mg of the active ingredient. tion of a medicament for treating the underlying emotion The present invention thus relates to the use of pipamperon dysregulation of pain disorders, characterized in that pipam or a pharmaceutically acceptable salt thereof for the prepara peron or said pharmaceutically acceptable salt thereof is tion of a medicament for treating the underlying emotion administered simultaneously with, separate from or prior to dysregulation of pain disorders, characterized in that pipam the administration of a vasopressin 1B receptor (V1B) 10 peron or said pharmaceutically acceptable salt thereof is antagonist compound to augment the therapeutic effect or to administered simultaneously with, separate from or prior to provide a faster onset of the therapeutic effect of said vaso the administration of a Voltage-gated calcium channel alpha pressin 1B receptor (V1B) antagonist compound, further (2)delta Subunit modulator compound to augment the thera characterized in that pipamperon is to be administered to a peutic effect or to provide a faster onset of the therapeutic patient in a daily dose ranging between 5 and 15 mg of the 15 effect of said Voltage-gated calcium channel alpha(2)delta active ingredient. Subunit modulator compound, further characterized in that According to a preferred embodiment, the invention relates pipamperon is to be administered to a patient in a daily dose to the uses as described above, wherein said vasopressin 1B ranging between 5 and 15 mg of the active ingredient. receptor (V1B) antagonist compound is SSR1494.15 or a According to a preferred embodiment, the invention relates pro-drug or an active metabolite thereof, or a pharmaceuti- 20 to the uses as described above, wherein said Voltage-gated cally acceptable salt thereof. calcium channel alpha(2)delta Subunit modulator compound The invention also relates to a pharmaceutical composition is pregabalin or PD-200.390; or a pro-drug or an active comprising (a) pipamperon, and (b) a vasopressin 1B receptor metabolite thereof, or a pharmaceutically acceptable salt (V1B) antagonist compound, preferably SSR1494.15 or a thereof. More preferably, said Voltage-gated calcium channel pro-drug or an active metabolite thereof, or a pharmaceuti- 25 alpha(2)delta Subunit modulator compound is pregabalin, and cally acceptable salt thereof, as a combined preparation for is to be administered in a daily dose ranging between 50 and simultaneous, separate or sequential use for treating the 600 mg of the active ingredient. underlying emotion dysregulation of a mental disease or dis The invention also relates to a pharmaceutical composition order which is chosen from the group consisting of mood comprising (a) pipamperon, and (b) a Voltage-gated calcium disorders, anxiety disorders, eating disorders, premenstrual 30 channel alpha(2)delta Subunit modulator compound, prefer syndrome, Somatoform disorders (excluding pain disorders), ably pregabalin or PD-200.390; or a pro-drug or an active factitious disorders, dissociative disorders, sexual and gender metabolite thereof, or a pharmaceutically acceptable salt identity disorders, sleep disorders, adjustment disorders, thereof, as a combined preparation for simultaneous, separate impulse control disorders, Substance-related disorders, per or sequential use for treating the underlying emotion dysregu Sonality disorders, bereavement, occupational problem, 35 lation of amental disease or disorder which is chosen from the problems related to abuse or neglect and pain disorders. group consisting of mood disorders, anxiety disorders, eating 98: Combination Therapy with a Voltage-Gated Calcium disorders, premenstrual syndrome, Somatoform disorders Channel C.(2)ö Subunit Modulator Compound (excluding pain disorders), factitious disorders, dissociative The mental disorders which can be treated using com disorders, sexual and gender identity disorders, sleep disor pounds having a high selective affinity for the 5-HT2A and 40 ders, adjustment disorders, impulse control disorders, Sub D4 receptor, for instance pipamperon, in a combination stance-related disorders, personality disorders, bereavement, therapy with a Voltage-gated calcium channel alpha(2)delta occupational problem, problems related to abuse or neglect Subunit modulator compound, are chosen from the group of and pain disorders. diseases or disorders consisting of mood disorders, anxiety The invention also relates to a pharmaceutical composition disorders, eating disorders, premenstrual syndrome, Somato- 45 as described above wherein pipamperon is provided in a form disorders (excluding pain disorders), factitious disor unitary dose of between 5 and 15 mg of the active ingredient ders, dissociative disorders, sexual and gender identity disor and wherein said Voltage-gated calcium channel alpha(2) ders, sleep disorders, adjustment disorders, impulse control delta Subunit modulator compound is pregabalin, preferably disorders, Substance-related disorders, personalty disorders, provided in a unitary dose of between 50 and 600 mg of the bereavement, occupational problem, problems related to 50 active ingredient. abuse or neglect and pain disorders. 99: Combination Therapy with a Vomeropherin Compound The present invention thus relates to the use of pipamperon The mental disorders which can be treated using com or a pharmaceutically acceptable sat thereof for the prepara pounds having a high selective affinity for the 5-HT2A and tion of a medicament for treating the underlying emotion D4 receptor, for instance pipamperon, in a combination dysregulation of a non-cognitive mental disease or disorder 55 therapy with a Vomeropherin compound, are chosen from the selected from the group of diseases and disorders consisting group of diseases or disorders consisting of anxiety disorders, of mood disorders, anxiety disorders, eating disorders, pre eating disorders, premenstrual syndrome, Somatoform disor menstrual syndrome, Somatoform disorders (excluding pain ders (excluding pain disorders), factitious disorders, disso disorders), factitious disorders, dissociative disorders, sexual ciative disorders, sexual and gender identity disorders, sleep and gender identity disorders, sleep disorders, adjustment 60 disorders, adjustment disorders, impulse control disorders, disorders, impulse control disorders, Substance-related disor personality disorders, bereavement, occupational problem ders, personality disorders, bereavement, occupational prob and problems related to abuse or neglect. lem and problems related to abuse or neglect, characterized in The present invention thus relates to the use of pipamperon that pipamperon or said pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof for the prepara thereof is administered simultaneously with, separate from or 65 tion of a medicament for treating the underlying emotion prior to the administration of a Voltage-gated calcium channel dysregulation of a non-cognitive mental disease or disorder alpha(2)delta Subunit modulator compound to augment the selected from the group of diseases and disorders consisting US 8,304,431 B2 121 122 of anxiety disorders, eating disorders, premenstrual Syn strual syndrome, Somatoform disorders (excluding pain dis drome. Somatoform disorders (excluding pain disorders), fac orders), factitious disorders, dissociative disorders, adjust titious disorders, dissociative disorders, sexual and gender ment disorders, impulse control disorders, attention-deficit identity disorders, sleep disorders, adjustment disorders, disorders, Substance-related disorders, personality disorders impulse control disorders, personality disorders, bereave and problems related to abuse or neglect, characterized in that ment, occupational problem and problems related to abuse or pipamperon or said pharmaceutically acceptable salt thereof neglect, characterized in that pipamperon or said pharmaceu is administered simultaneously with, separate from or prior to tically acceptable salt thereof is administered simultaneously the administration of a dopamine releaser compound to aug with, separate from or prior to the administration of vomero ment the therapeutic effect or to provide a faster onset of the pherin compound to augment the therapeutic effect or to 10 therapeutic effect of said dopamine releaser compound, fur provide a faster onset of the therapeutic effect of said vomero ther characterized in that pipamperon is to be administered to pherin compound, further characterized in that pipamperon is a patient in a daily dose ranging between 5 and 15 mg of the to be administered to a patient in a daily dose ranging between active ingredient. 5 and 15 mg of the active ingredient. The present invention thus relates to the use of pipamperon According to a preferred embodiment, the invention relates 15 or a pharmaceutically acceptable salt thereof for the prepara to the use as described above, wherein said vomeropherin tion of a medicament for treating the underlying emotion compound is PH94B or a pro-drug or an active metabolite dysregulation of pain disorders, characterized in that pipam thereof, or a pharmaceutically acceptable salt thereof. peron or said pharmaceutically acceptable salt thereof is The invention also relates to a pharmaceutical composition administered simultaneously with, separate from or prior to comprising (a) pipamperon, and (b) Vomeropherin com the administration of a dopamine releaser compound to aug pound, preferably PH94B or a pro-drug or an active metabo ment the therapeutic effect or to provide a faster onset of the lite thereof, or a pharmaceutically acceptable Salt thereof, as therapeutic effect of said dopamine releaser compound, fur a combined preparation for simultaneous, separate or sequen ther characterized in that pipamperon is to be administered to tial use for treating the underlying emotion dysregulation of a a patient in a daily dose ranging between 5 and 15 mg of the non-cognitive mental disease or disorder which is chosen 25 active ingredient. from the group consisting of anxiety disorders, eating disor The present invention thus relates to the use of pipamperon ders, premenstrual syndrome, Somatoform disorders (exclud or a pharmaceutically acceptable salt thereof for the prepara ing pain disorders), factitious disorders, dissociative disor tion of a medicament for treating the underlying emotion ders, sexual and gender identity disorders, sleep disorders, dysregulation of Parkinson disease, characterized in that adjustment disorders, impulse control disorders, personality 30 pipamperon or said pharmaceutically acceptable salt thereof disorders, bereavement, occupational problem and problems is administered simultaneously with, separate from or prior to related to abuse or neglect. the administration of a dopamine releaser compound to aug Also, the invention relates in particular to the use as ment the therapeutic effect or to provide a faster onset of the described before, wherein said second compound is chosen therapeutic effect of said dopamine releaser compound, fur from the group consisting of fluvoxamine controlled release, 35 ther characterized in that pipamperon is to be administered to phenserine tartrate, atomoxetine hydrochloride, bupropion a patient in a daily dose ranging between 5 and 15 mg of the (controlled-release formulation), ropinirole HCL (con active ingredient. trolled-release formulation), INN 00835, galantamine (ex According to a preferred embodiment, the invention relates tended release formulation), paliperidone, tomoxetine, to the uses as described above, wherein said dopamine (recep aprepitant, rivastigmine tartrate, ORG 34517/34850, sune 40 tor) agonist compound is amantadine, or a pro-drug or an pitron, Sumanirole, milnacipran, idazoxan, Xaliproden, SR active metabolite thereof, or a pharmaceutically acceptable 58611, befioxatone, litoxetine, tianeptine, agomelatine, SPD salt thereof. Preferably, amantadine is to be administered in a 503, flesinoxan, bifeprunoX, ramelteon, etilevodopa, rasa daily dose of between 100 and 300 mg of the active ingredi giline (TVP-1012) and desvenlafaxine. ent. Also, the invention relates in particular to the use as 45 The invention a so relates to a pharmaceutical composition described before, wherein said second compound is chosen comprising (a) pipamperon, and (b) a dopamine (receptor) from the group consisting of galantamine (extended release agonist, preferably amantadine, or a pro-drug or an active formulation), R121919, risperidone, paliperidone and metabolite thereof, or a pharmaceutically acceptable salt R228060 (YKP-10A). thereof, as a combined preparation for simultaneous, separate 100: Combination Therapy with a Dopamine Releaser 50 or sequential use for treating the underlying emotion dysregu The mental disorders which can be treated using com lation of amental disease or disorder which is chosen from the pounds having a high selective affinity for the 5-HT2A and group of diseases or disorders consisting of mood disorders, D4 receptor, for instance pipamperon, in a combination anxiety disorders, eating disorders, premenstrual syndrome, therapy with a dopamine releaser, are chosen from the group Somatoform disorders (excluding pain disorders), factitious of diseases or disorders consisting of mood disorders, anxiety 55 disorders, dissociative disorders, adjustment disorders, disorders, eating disorders, premenstrual syndrome, Somato impulse control disorders, attention-deficit disorders, Sub form disorders (excluding pain disorders), factitious disor stance-related disorders, personality disorders, problems ders, dissociative disorders, adjustment disorders, impulse related to abuse or neglect, pain disorders and Parkinson control disorders, attention-deficit disorders, Substance-re disease. lated disorders, personality disorders, problems related to 60 The invention also relates to a pharmaceutical composition abuse or neglect, pain disorders and Parkinson disease. as described above wherein pipamperon is provided in a The present invention thus relates to the use of pipamperon unitary dose of between 5 and 15 mg of the active ingredient or a pharmaceutically acceptable salt thereof for the prepara and wherein said dopamine (receptor) agonist is amantadine, tion of a medicament for treating the underlying emotion preferably provided in a unitary dose of between 100 and 300 dysregulation of a non-cognitive mental disease or disorder 65 mg of the active ingredient. selected from the group of diseases and disorders consisting From the above it will be apparent that the numbering of the mood disorders, anxiety disorders, eating disorders, premen grouping according to the action on the pathway or system US 8,304,431 B2 123 124 corresponds to the numbering of the columns in Table 5 and FIG.3: Remission rates (HDRS-17<=7): combo treatment the numbering of the pharmalogical profile in Table 6. pipamperon as add-on—citalopram VS SNRI (veniafaxine) VS The disclosure of all patents, publications (including pub SSRIs vs placebo in Major Depression. lished patent publications), and database accession numbers FIG. 4: Fore-going treatment during 1-5 days with pipam and depository accession numbers referenced in this specifi peron followed with the combination treatment of pipam cation are specifically incorporated herein by reference in peron and citalopram. their entirety to the same extent as if each such individual FIG. 5: HDRS-17 change from baseline: combo treatment patent, publication, and database accession number, and pipamperon-citalopram with a fore-going treatment of 4 days depository accession number were specifically and individu with pipamperon vs SNRI (duloxetine) in Major Depression. ally indicated to be incorporated by reference. 10 The invention, now being generally described, will be more FIG. 6: Remission rates (HDRS-17<=7): combo pipam readily understood by reference to the following tables and peron-citalopram with a fore-going treatment of 4 days with examples, which are included merely for purposes of illus pipamperon vs SNRI (venlafaxine) in Major Depression. tration of certain aspects and embodiments of the present FIG. 7: Fore-going treatment during 6-8 days with pipam invention and are not intended to limit the invention. 15 peron followed with the combination treatment of pipam peron and citalopram. SHORT DESCRIPTION OF THE TABLES AND FIG. 8: HDRS-17 change from baseline: combo treatment FIGURES pipamperon-citalopram with a fore-going treatment of 7 days with pipamperon vs SNRI (duloxetine) in Major Depression. Table 1: In Table 1, the pKi values of test compounds are given for each of the dopamine receptors, 5HT receptors, FIG.9: Fore-going and add-on treatment with pipamperon adrenergic receptors and the histaminel receptor. in MDD. Table 2: Set-up of a clinical trial comprising for treatment FIG.10: HDRS-17 change from baseline: fore-going and groups. add-on treatment with pipamperon and citalopram in com Table 3: Overview of a placebo, active and period con 25 parison with the SNRI dulloxetine in Major Depression. trolled clinical trial in a fore-going pipamperon-citalopram FIG. 11: Remission rates (HDRS-17<=7): fore-going and treatment in Major Depressive Disorder. add-on treatment with pipamperon and citalopram in com Table 4: POC process for major depressive disorder. parison with the SNRI venlafaxine in Major Depression. Table 5: Summary of diseases and disorders relative to FIG. 12:Y-BOCS total score: fore-going and add-on treat known psycho-tropics. 30 ment with pipamperon and citalopram in comparison with the Table 6: Overview of Pharmacological grouping, indicat SSRI fluvoxamine in OCD. ing pharmacological profile numbering (column 2), pharma FIG. 13: Y-BOCS obsession score: fore-going and add-on cological profile (column 3), main indication(s) (column 4). treatment with pipamperon and citalopram in comparison name of the compound (column 4), the dose range (column with the SSRI fluvoxamine in OCD. 5), and the company producing or selling said compound 35 (column 6). Compounds indicated by hatching are preferred. FIG. 14: Y-BOOS compulsion score: fore-going and add FIG. 1: Add-on treatment with pipamperon after treatment on treatment with pipamperon and citalopram in comparison with citalopram. with the SSR fluvoxamine in OCD. FIG. 2: HDRS-17 change from baseline: combo treatment FIG. 15: CGI-severity score: fore-going and add-on treat pipamperon as add-on-citalopram VS SNRI (duloxetine) in ment with pipamperon and citalopram in comparison with the Major Depression. SSRI in panic disorder. TABLE 1 D1 D2 D3 D4 5HT 5HT 5HT 5HT. 5HT. 5HT24 5HT2

ORG5222 8-9 8-9 8-9 8-9 8-9 8-9 8-9 7-8 O >9 >9 Zotepine O 8-9 8-9 7-8 6-7 7-8 7-8 6-7 O 8-9 O Fluparoxan O <6 <6 O 6-7 <6 <6 O O <6 O Olanzapine 7-8 7-8 7-8 7-8 <6 6-7 6-7 <6 6-7 8-9 8-9 Clozapine 7-8 6-7 6-7 7-8 6-7 6-7 6-7 6-7 6-7 8-9 8-9 S16924 O 7-8 7-8 7-8 8-9 O O O O >9 8-9 S18327 7-8 7-8 6-7 8-9 7-8 O O O O 8-9 O 6-7 6-7 6-7 <6 <6 O O O O 8-9 O GGR218231 <6 7-8 >9 <6 6-7 <6 <6 O O <6 <6 Sertindole 7-8 8-9 8-9 7-8 6-7 7-8 7-8 6-7 6-7 >9 O MDL100,907 6-7 <6 <6 6-7 <6 O O O O >9 O Haloperidol 8-9 >9 8-9 8-9 <6 6-7 <6 <6 <6 6-7 <6 Tiospirone 7-8 8-9 8-9 8-9 8-9 O O O O >9 O Raciopride <6 8-9 8-9 <6 <6 O O O O 6-7 O Fluspirilene O >9 8-9 8-9 7-8 <6 <6 <6 O <6 O Ocaperidone 7-8 >9 8-9 8-9 7-8 O O O O >9 O Risperidone 7-8 8-9 7-8 8-9 6-7 8-9 6-7 <6 <6 >9 O S33O84 6-7 7-8 >9 <6 <6 6-7 6-7 O O 6-7 6-7 L741626 6-7 8-9 7-8 6-7 <6 <6 <6 O O 6-7 6-7 Seroquel 6-7 6-7 6-7 <6 6-7 <6 <6 <6 <6 6-7 6-7 Yohimbine O 6-7 <6 O 7-8 6-7 7-8 O O <6 O Ziprasidone 8-9 8-9 7-8 7-8 8-9 >9 8-9 6-7 O >9 8-9 Pipamperon O 6-7 6-7 8-9 <6 6-7 6-7 <6 <6 8-9 O

US 8,304,431 B2 127 128 TABLE 2-continued

ACUTEPHASE** EXTENSION PHASE*** FOLLOW-UP PHASE

VISITS

V1 V2 V3 V4 VS V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 V16 V17 V18 V19 Day/Week Month

Screen Base minus line D7 DO D4 D7 W2. W3 W4 W6 W8 W10 W12 W16 W2O W24 M8 M10 M12 W1 W2 Q-LES Q: 888 Treatment regimen: A: PLC - PLC B: 2 x (PLC + PIP (4 mg))/d C: 2 x (CIT (10 mg)+PIP (4 mg));d D: 2 x (CIT (10 mg)+PLC) id *Neuronal E-Clinical Trial = Vesalius Expert Development for this Trial which includes the bottom-up measurement of **Entering Acute Phase; only NON-placebo responders as defined by the DSM-IV criteria of efficacy ***Entering Extension Phase; only remittors as defined by the DSM-IV criteria of efficacy ****CGI-S: Clinical Global Impressions-Improvement Scale *****Q-LES-Q: Quality of Life, Enjoyment and Satisfaction Questionnaire

TABLE 3

FOREGOING PIPAMPERON-CITALOPRAMTREATMENT IN MAJOR DEPRESSIVE DISORDER A PLACEBO, ACTIVE AND PERIODE CONTROLLED CLINICAL TRIAL

ACUTEPHASE** EXTENSION PHASE*** FOLLOW-UP PHASE

VISITS

V1 V2 V3 V4 VS V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 V16 V17 V18 V19 DAY, WEEKAMONTH

SCREEN BASE minus LINE D7 DO D4 D7 W2. W3 W4 W6 W8 W10 W12 W16 W2O W24 M8 M10 M12 W1 W2

TREAT MENT GROUP

Group PLC - 2 x 2 x PLC - PLC Pip - PLC (PLC + (CIT PLC PLC Active? PIP (10 Day 4 (4 mg) + mg))/ PIP d (4 mg))/ d Group PLC - 2 x PLC - PLC Pip - PLC (CIT PLC PLC Active? (10 Day 0 mg) + PIP (4 mg))/ d Group PLC - 2 x PLC - PLC Plc - PLC (CIT PLC PLC Active? (10 Day 0 mg) + PLC)/ d Group PLC - PLC - PLC Placebo PLC PLC PLC In- X formed Consent NECT: X X X X X X X X X X X X X X X X X X X Vital X X X X X X X X X X X X X X X X X X X Signs Weight LAB X X X X X X US 8,304,431 B2

TABLE 3-continued

FOREGOING PIPAMPERON-CITALOPRAMTREATMENT IN MAJOR DEPRESSIVE DISORDER A PLACEBO, ACTIVE AND PERIODE CONTROLLED CLINICAL TRIAL

ACUTEPHASE** EXTENSION PHASE*** FOLLOW-UP PHASE

VISITS

V1 V2 V3 V4 VS V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 V16 V17 W18 V19 DAYFWEEKAMONTH

SCREEN BASE minus LINE D7 DO D4 D7 W2. W3 W4 W6 W8 W10 W12 W16 W2O W24 M8 M10 M12 W1 W2

ECG X X X X Phys X X X X X Exam Alci X X X X Drugs Screen CGI-S X X X X X X X X X X X X X X X X X * * * * Q- X X X X X X X X X X X X X X X LES-Q *Neuronal E-Clinical Trial = Vesalius Expert Development for this Trial which includes the bottom-up measurement of: n- and exclusion criteria Functional status evaluation Medical history (Pre-)treatment signs & symptoms DSM-IV rules for diagnosis & efficacy ting Scales: HDRS-28, MADRS, HAMA Medical resource utulisation Pre-trial & Concomittant Drug administration (Serious) Adverse events Admission to the acute and extension phase of treatment Right flow of the trial **Entering AcutePhase: only NON-placebo responders as defined by the DSM-IV criteria of efficacy ***Entering Extension Phase: only remittors as defined by the DSM-IV criteria of efficacy ****Q-LES-Q: Quality of Life, Enjoyment and Satisfaction Questionnaire

TABLE 4

DAY minus D7 DO =>D4

TREATMENTGROUP Placebo (PLC) PLC + PLC 2x (PLC + PLC) 2 x (PLC + PC) PIP - Active/Day 4 PLC + PLC 2 x (PLC + PIP (4 mg))/d 2 x (CIT (10 mg) + PIP (4 mg))/d PIP - Active/Day 0 PLC + PLC 2 x (CIT (10 mg) + PIP (4 mg))/d 2 x (CIT (10 mg) + PIP (4 mg))/d PLC - Active/Day O PLC + PLC 2 x (CIT (10 mg) + PLC)/d 2 x (CIT (10 mg) + PLC)/d

TABLE 5

*SEE GLOSSARY HEREUNDER

MEDICAMENT

92 91 90 85 60 62 61 82 51 MONO COMBO’s S- 5-HT2A/D4*-Antagonist + CNS Compound

HT2A MAO-A* & D4: MAO-B* MEDICAL Antag- reuptake INDICATION onist SSRI* SNRI* SNDRI* SDRI* NARI* NDRI* NaSSA RIMA inhibitor

DISORDER WITH X X X X X X X X X X ANUNDERLYING EMOTION DYSREGULATION NON-COGNITIVE US 8,304,431 B2 131 132 TABLE 5-continued

*SEE GLOSSARY HEREUNDER

MENTAL DISORDERS (excl. Pain Disorder) mood disorders anxiety disorders X X psychotic disorders eating disorders premenstrual syndrome Somatoform disorders (excluding Pain Disorder) factitious disorders dissociative disorders X X X X sexual and gender identity disorders sleep disorders adjustment disorders impulse control disorders pervasive development disorders attention-deficit X disorders disruptive behaviour disorders Substance-related disorders personality disorders psychological factors affecting medical conditions malingering antisocial behaviour bereavement occupational problem identity problem phase of life problem academic problem problems related to abuse or neglect PAIN DISORDER COGNITIVE DISORDERS

elirium Alzheimer Disease Substance-induced persisting ementia vascular dementia ementia due to HIV disease ementia due to head trauma ementia due to Parkinson Disease ementia due to Huntington Disease ementia due to Pick Disease ementia due to Creutzfeldt-Jacob Disease amnestic disorders ue to a general medical condition Substance-induced persisting amnestic disorder mild cognitive impairment disorder other cognitive disorders US 8,304,431 B2 133 134 TABLE 5-continued

*SEE GLOSSARY HEREUNDER

PARKINSON DISEASE

MEDICAMENT

6 7 MONO COMBO’s S 5-HT2A/D4*-Antagonist + CNS Compound

HT2A 5-HT1: D4: auto MEDICAL Antag 5-HTA1* 5-HTA1* 5-HT1B: 5-HT2B: 5-HT2C: 5HT3: 5HT6: receptor INDICATION onist agonist antagonist antagonist antagonist antagonist antagonist antagonist agonist

DISORDER WITH X ANUNDERLYING EMOTION DYSREGULATION NON-COGNITIVE MENTAL DISORDERS (excl. Pain Disorder) mood disorders anxiety disorders psychotic disorders eating disorders premenstrual syndrome Somatoform disorders (excluding Pain Disorder) factitious disorders dissociative disorders sexual and gender identity disorders sleep disorders adjustment disorders impulse control X disorders pervasive development disorders attention-deficit disorders disruptive behaviour disorders Substance-related disorders personality disorders psychological factors affecting medical conditions malingering antisocial behaviour bereaweilent occupational problem identity problem phase of life problem academic problem problems related to abuse or neglect PAINDISORDER COGNITIVE DISORDERS delirium Alzheimer Disease Substance-induced persisting dementia vascular dementia dementia due to HIV disease dementia due to head trauma dementia due to Parkinson Disease dementia due to X Huntington Disease US 8,304,431 B2 135 136 TABLE 5-continued

*SEE GLOSSARY HEREUNDER dementia due to Pick Disease dementia due to Creutzfeldt-Jacob Disease amnestic disorders due to a general medical condition Substance-induced persisting amnestic disorder mild cognitive impairment disorder other cognitive disorders PARKINSON DISEASE

MEDICAMENT

44 93 69 95 76 55 MONO COMBO’s S 5-HT2A/D4*-Antagonist + CNS compound

HT2A Increase D4: 5-HT's brain Substance MEDICAL Antag reuptake concentrations P NK2* tachykinin MCH*-receptor INDICATION onist enhancer of 5-HT3 Antagonist Antagonist antagonist peptide antagonist

DISORDER WITH X X X X X ANUNDERLYING EMOTION DYSREGULATION NON-COGNITIVE MENTAL DISORDERS (excl. Pain Disorder) mood disorders anxiety disorders psychotic disorders eating disorders premenstrual syndrome Somatoform disorders (excluding Pain Disorder) factitious disorders dissociative disorders sexual and gender identity disorders sleep disorders adjustment disorders impulse control disorders pervasive development disorders attention-deficit disorders disruptive behaviour disorders Substance-related disorders personality disorders psychological factors affecting medical conditions malingering antisocial behaviour bereavement occupational problem identity problem phase of life problem academic problem problems related to abuse or neglect US 8,304,431 B2 137 138 TABLE 5-continued

*SEE GLOSSARY HEREUNDER

PAIN DISORDER COGNITIVE DISORDERS

elirium Alzheimer Disease Substance-induced persisting dementia vascular dementia ementia due to HIV disease ementia due to head trauma ementia due to Parkinson Disease ementia due to Huntington Disease ementia due to Pick Disease ementia due to Creutzfeldt-Jacob Disease amnestic disorders ue to a general medical condition Substance-induced persisting amnestic disorder mild cognitive impairment disorder other cognitive disorders PARKINSON DISEASE

MEDICAMENT

MONO 56 41 26 40 S4 19 14 S COMBO’s HT2A 5-HT2A/D4*-Antagonist + CNS compound

D4: beta-3- MEDICAL Antag MT: GR: CRF-18 GPCR: MC4* adrenoceptor alpha 2 INDICATION onist agonist antagonist antagonist modulator antagonists agonist antagonists

DISORDER WITH X X X X ANUNDERLYING EMOTION DYSREGULATION NON-COGNITIVE MENTAL DISORDERS (excl. Pain Disorder) mood disorders anxiety disorders psychotic disorders eating disorders premenstrual syndrome Somatoform disorders (excluding Pain Disorder) factitious disorders dissociative disorders sexual and gender identity disorders sleep disorders adjustment disorders impulse control disorders pervasive development disorders attention-deficit disorders disruptive behaviour disorders Substance-related X disorders US 8,304,431 B2 139 140 TABLE 5-continued

*SEE GLOSSARY HEREUNDER personality disorders X X X X psychological factors X affecting medical conditions malingering antisocial behaviour bereaweilent X X X X occupational problem X X X X X X identity problem phase of life problem academic problem problems related to X X X X abuse or neglect PAINDISORDER X X X X COGNITIVE DISORDERS delirium Alzheimer Disease Substance-induced persisting dementia vascular dementia dementia due to HIV disease dementia due to head trauma dementia due to Parkinson Disease dementia due to Huntington Disease dementia due to Pick Disease dementia due to Creutzfeldt-Jacob Disease amnestic disorders due to a general medical condition Substance-induced persisting amnestic disorder mild cognitive impairment disorder other cognitive disorders PARKINSON DISEASE

MEDICAMENT

13 86 97 12 71 75 98 MONO COMBO’s 5-HT2A/D4*-Antagonist + CNS compound

Second X Voltage-gated messenger Adrenergic calcium channel MEDICAL Antag alpha 1 beta V1B: transmitter NMDA: PDE4: alpha(2)delta Subunit INDICATION onist antagonists agonist antagonist releaser antagonist inhibitor modulator

DISORDER WITH X X X X X X ANUNDERLYING EMOTION DYSREGULATION NON-COGNITIVE MENTAL DISORDERS (excl. Pain Disorder) mood disorders X X X X anxiety disorders X X X X psychotic disorders eating disorders X X X X premenstrual syndrome X X X X Somatoform disorders X X X X (excluding Pain Disorder) factitious disorders X X X X dissociative disorders X X X X US 8,304,431 B2 141 142 TABLE 5-continued

*SEE GLOSSARY HEREUNDER sexual and gender X X X identity disorders sleep disorders X adjustment disorders X X X impulse control X X X X disorders pervasive development disorders attention-deficit disorders disruptive behaviour disorders Substance-related X disorders personality disorders X X X psychological factors affecting medical conditions malingering antisocial behaviour bereaweilent X X X occupational problem X X X X X X identity problem phase of life problem academic problem problems related to X X X abuse or neglect PAINDISORDER X X X COGNITIVE XX DISORDERS delirium Alzheimer Disease X Substance-induced X persisting dementia vascular dementia X ementia due to X HIV disease ementia due to X head trauma ementia due to X Parkinson Disease ementia due to X X Huntington Disease ementia due to X Pick Disease ementia due to X Creutzfeldt-Jacob Disease amnestic disorders X ue to a general medical condition Substance-induced X persisting amnestic disorder mild cognitive X impairment disorder other cognitive X disorders PARKINSON DISEASE

MEDICAMENT

83 78 88 39 57 67 35 MONO COMBO’s 5-HT2A/D4*-Antagonist + CNS compound

nicotinic Prodrug Sigma Glutamate acetylcholine MEDICAL Antag SCT 11: of receptor receptor GR receptor GABA-A* INDICATION onist modulation uridine agonist antagonist agonist antagonist modulator

DISORDER WITH X X X X X X X ANUNDERLYING EMOTION US 8,304,431 B2 143 144 TABLE 5-continued

*SEE GLOSSARY HEREUNDER

DYSREGULATION NON-COGNITIVE MENTAL DISORDERS (excl. Pain Disorder) mood disorders anxiety disorders psychotic disorders eating disorders premenstrual syndrome Somatoform disorders (excluding Pain Disorder) factitious disorders dissociative disorders X X X sexual and gender identity disorders sleep disorders adjustment disorders impulse control X X X disorders pervasive development disorders attention-deficit X disorders disruptive behaviour disorders Substance-related disorders personality disorders psychological factors affecting medical conditions malingering antisocial behaviour bereaweilent occupational problem X X X X X X identity problem phase of life problem academic problem problems related to abuse or neglect PAINDISORDER COGNITIVE DISORDERS delirium Alzheimer Disease Substance-induced persisting dementia vascular dementia dementia due to HIV disease dementia due to head trauma dementia due to Parkinson Disease dementia due to Huntington Disease dementia due to Pick Disease dementia due to Creutzfeldt-Jacob Disease amnestic disorders due to a general medical condition Substance-induced persisting amnestic disorder mild cognitive impairment disorder other cognitive disorders PARKINSON DISEASE US 8,304,431 B2 145 146 TABLE 5-continued

*SEE GLOSSARY HEREUNDER

MEDICAMENT

36 99 74 77 89 94 87 MONO COMBO’s S 5-HT2A/D4*-Antagonist + CNS compound

HT2A Phospholipase D4: A2 inhibitor sigma Secretin MEDICAL Antag GABA-B WOleO opoid with caspase receptor pancreatic INDICATION onist antagonist pherin agonist inhibitor activity antagonist Sulfonamide hormone

DISORDER WITH X X X X X ANUNDERLYING EMOTION DYSREGULATION NON-COGNITIVE MENTAL DISORDERS (excl. Pain Disorder) mood disorders anxiety disorders psychotic disorders eating disorders premenstrual syndrome Somatoform disorders (excluding Pain Disorder) factitious disorders dissociative disorders X sexual and gender XX identity disorders sleep disorders adjustment disorders impulse control disorders pervasive development disorders attention-deficit disorders disruptive behaviour X X disorders Substance-related disorders personality disorders psychological factors affecting medical conditions malingering antisocial behaviour bereaweilent occupational problem X X X X X identity problem phase of life problem academic problem problems related to X X abuse or neglect PAINDISORDER X X COGNITIVE DISORDERS delirium Alzheimer Disease Substance-induced persisting dementia vascular dementia dementia due to HIV disease dementia due to head trauma dementia due to Parkinson Disease dementia due to Huntington Disease dementia due to Pick Disease dementia due to Creutzfeldt-Jacob US 8,304,431 B2 147 148 TABLE 5-continued

*SEE GLOSSARY HEREUNDER Disease amnestic disorders due to a general medical condition Substance-induced persisting amnestic disorder mild cognitive impairment disorder other cognitive disorders PARKINSON DISEASE

MEDICAMENT

MONO 84 28 29 70 65 21 COMBO’s HT2A 5-HT2A/D4*-Antagonist + CNS compound

D4: neurotensin MEDICAL Antag D2:- D3*- NK3* receptor CB1* INDICATION onist SDA: antagonist antagonist antagonist antagonist antagonist

DISORDER WITH ANUNDERLYING EMOTION DYSREGULATION NON-COGNITIVE MENTAL DISORDERS (excl. Pain Disorder) mood disorders anxiety disorders psychotic disorders eating disorders premenstrual syndrome Somatoform disorders (excluding Pain Disorder) factitious disorders dissociative disorders X X X X X sexual and gender identity disorders sleep disorders adjustment disorders impulse control disorders pervasive development disorders attention-deficit disorders disruptive behaviour disorders Substance-related disorders personality disorders psychological factors affecting medical conditions malingering antisocial behaviour bereaweilent occupational problem identity problem phase of life problem academic problem problems related to X X X X X X abuse or neglect PAINDISORDER X X X X X X COGNITIVE DISORDERS delirium Alzheimer Disease Substance-induced persisting dementia US 8,304,431 B2 149 150 TABLE 5-continued

*SEE GLOSSARY HEREUNDER vascular dementia dementia due to HIV disease dementia due to head trauma dementia due to Parkinson Disease dementia due to Huntington Disease dementia due to Pick Disease dementia due to Creutzfeldt-Jacob Disease amnestic disorders X due to a general medical condition Substance-induced X persisting amnestic disorder mild cognitive X impairment disorder other cognitive X disorders PARKINSON X DISEASE

MEDICAMENT

MONO 15 34 18 79 81 16 73 27 S- COMBO’s HT2A 5-HT2A/D4*-Antagonist + CNS compound D4: AMPA androgen prosta- opioid D1: MEDICAL Antag- receptor GABA-A* receptor glandin Psycho- ampheta- receptor receptor INDICATION onist mediator agonist modulator E1 stimulant mine inhibitor agonist

DISORDER WITH X X X X X X X X X ANUNDERLYING EMOTION DYSREGULATION NON-COGNITIVE MENTAL DISORDERS (excl. Pain Disorder) mood disorders anxiety disorders psychotic disorders eating disorders premenstrual syndrome Somatoform disorders (excluding Pain Disorder) factitious disorders dissociative disorders sexual and gender identity disorders sleep disorders adjustment disorders impulse control disorders pervasive development disorders attention-deficit disorders disruptive behaviour disorders Substance-related disorders personality disorders psychological factors affecting medical conditions malingering antisocial behaviour bereavement occupational problem US 8,304,431 B2 151 152 TABLE 5-continued

*SEE GLOSSARY HEREUNDER identity problem phase of life problem academic problem problems related to abuse or neglect PAIN DISORDER X COGNITIVE DISORDERS delirium Alzheimer Disease Substance-induced persisting dementia vascular dementia dementia due to HIV disease dementia due to head trauma dementia due to Parkinson Disease dementia due to Huntington Disease dementia due to Pick Disease dementia due to Creutzfeldt-Jacob Disease amnestic disorders X X due to a general medical condition Substance-induced X X persisting amnestic disorder mild cognitive X X impairment disorder other cognitive X X disorders PARKINSON X DISEASE

MEDICAMENT

MONO 38 50 43 10 23 66 58 S- COMBO’s HT2A 5-HT2A/D4*-Antagonist + CNS compound D4: glucocorticoid MAO: acetylholin choline mimics the MEDICAL Antag- synthesis reuptake Hormonal eStrase- uptake effects of INDICATION onist inhibitor inhibitor Substance Inhibitor enhancer NGF: NGF:

DISORDER WITH X X X X X X X X ANUNDERLYING EMOTION DYSREGULATION NON-COGNITIVE MENTAL DISORDERS (excl. Pain Disorder) mood disorders anxiety disorders X psychotic disorders eating disorders premenstrual syndrome X Somatoform disorders (excluding Pain Disorder) factitious disorders dissociative disorders sexual and gender identity disorders sleep disorders adjustment disorders impulse control disorders pervasive development X disorders US 8,304,431 B2 153 154 TABLE 5-continued

*SEE GLOSSARY HEREUNDER attention-deficit disorders disruptive behaviour disorders Substance-related disorders personality disorders psychological factors affecting medical conditions malingering antisocial behaviour bereaweilent occupational problem identity problem phase of life problem academic problem problems related to abuse or neglect PAINDISORDER COGNITIVE DISORDERS delirium Alzheimer Disease Substance-induced persisting dementia vascular dementia dementia due to HIV disease dementia due to head trauma dementia due to Parkinson Disease dementia due to Huntington Disease dementia due to Pick Disease dementia due to Creutzfeldt-Jacob Disease amnestic disorders X X X X due to a general medical condition Substance-induced persisting amnestic disorder mild cognitive impairment disorder other cognitive disorders PARKINSON DISEASE

MEDICAMENT

59 17 45 68 33 32 MONO COMBO’s 5-HT2A/D4*-Antagonist + CNS compound

Muscarinic protect receptor amyloid dopaminergic increasing nicotinic MEDICAL Antag partial aggregation and cholinergic insulin receptor GABA ERK* INDICATION onist agonist inhibitor leOS sensitivity agonists agonist activation

DISORDER WITH X X X X ANUNDERLYING EMOTION DYSREGULATION NON-COGNITIVE MENTAL DISORDERS (excl. Pain Disorder) mood disorders anxiety disorders psychotic disorders eating disorders US 8,304,431 B2 155 156 TABLE 5-continued

*SEE GLOSSARY HEREUNDER premenstrual syndrome X Somatoform disorders X (excluding Pain Disorder) factitious disorders dissociative disorders sexual and gender X identity disorders sleep disorders adjustment disorders impulse control X disorders pervasive development X disorders attention-deficit X disorders disruptive behaviour X disorders Substance-related X disorders personality disorders psychological factors affecting medical conditions malingering antisocial behaviour bereavement occupational problem identity problem phase of life problem academic problem problems related to abuse or neglect PAIN DISORDER COGNITIVE DISORDERS delirium Alzheimer Disease X X X X X Substance-induced X X X X X persisting dementia vascular dementia X X X X X ementia due to X X X X X HIV disease ementia due to X X X X X head trauma ementia due to X X X X X Parkinson Disease ementia due to X X X X X Huntington Disease ementia due to X X X X X Pick Disease ementia due to X X X X X Creutzfeldt-Jacob Disease amnestic disorders X X X X X X ue to a general medical condition Substance-induced X X X X X X persisting amnestic disorder mild cognitive X X X X X X impairment disorder other cognitive X X X X X X disorders US 8,304,431 B2 157 158 TABLE 5-continued

*SEE GLOSSARY HEREUNDER

PARKINSON DISEASE

MEDICAMENT

MONO 42 48 31 100 52 30 S COMBO’s HT2A 5-HT2A/D4*-Antagonist + CNS compound

D4: Calcium MEDICAL Antag H3: Channel Dopamine Dopamine MAO-B- DA* uptake INDICATION onist Antagonist Modulator Levodopa agonist releaser inhibitor inhibitor

DISORDER WITH X X X X X ANUNDERLYING EMOTION DYSREGULATION NON-COGNITIVE MENTAL DISORDERS (excl. Pain Disorder) mood disorders X X anxiety disorders X X psychotic disorders eating disorders X X premenstrual syndrome X X Somatoform disorders X X (excluding Pain Disorder) factitious disorders X X dissociative disorders X X X sexual and gender identity disorders sleep disorders adjustment disorders X X impulse control X X X disorders pervasive development disorders attention-deficit X X disorders disruptive behaviour disorders Substance-related X X disorders personality disorders X X psychological factors affecting medical conditions malingering antisocial behaviour bereaweilent occupational problem identity problem phase of life problem academic problem problems related to X X abuse or neglect PAINDISORDER X X COGNITIVE DISORDERS delirium Alzheimer Disease Substance-induced persisting dementia vascular dementia dementia due to HIV disease dementia due to head trauma dementia due to Parkinson Disease dementia due to Huntington Disease dementia due to X X Pick Disease US 8,304,431 B2 159 160 TABLE 5-continued

*SEE GLOSSARY HEREUNDER dementia due to X Creutzfeldt-Jacob Disease amnestic disorders X X due to a general medical condition Substance-induced X X persisting amnestic disorder mild cognitive X X impairment disorder other cognitive X X disorders PARKINSON DISEASE

MEDICAMENT

49 63 64 37 46 11 24 25 COMBO’s MONO 5-HT2A/D4*-Antagonist + CNS compound

S Glial-cell inhibitor of COX*- HT2A leO Line the mixed adenosine inhibiting D4: Lipid immuno Derived lineage A2a nitric. MEDICAL Antag- DNA philin leO Neurotrophic kinase receptor COX-2* oxide INDICATION onist Complex ligands modulator Factor family antagonist Inhibitor donators

DISORDER WITH X X X X X X X X X ANUNDERLYING EMOTION DYSREGULATION NON-COGNITIVE MENTAL DISORDERS (excl. Pain Disorder) mood disorders anxiety disorders X psychotic disorders eating disorders premenstrual syndrome Somatoform disorders (excluding Pain Disorder) factitious disorders dissociative disorders sexual and gender identity disorders sleep disorders adjustment disorders impulse control disorders pervasive development X disorders attention-deficit X disorders disruptive behaviour X disorders Substance-related X disorders personality disorders psychological factors affecting medical conditions malingering antisocial behaviour bereavement occupational problem identity problem phase of life problem academic problem problems related to abuse or neglect US 8,304,431 B2 161 162 TABLE 5-continued

*SEE GLOSSARY HEREUNDER

PAIN DISORDER COGNITIVE DISORDERS delirium Alzheimer Disease Substance-induced persisting dementia vascular dementia ementia due to HIV disease ementia due to head trauma ementia due to Parkinson Disease ementia due to Huntington Disease ementia due to Pick Disease ementia due to Creutzfeldt-Jacob Disease amnestic disorders ue to a general medical condition Substance-induced persisting amnestic disorder mild cognitive impairment disorder other cognitive disorders PARKINSON X X X X X DISEASE

MEDICAMENT

72 47 22 96 53 COMBO’s

MONO 5-HT2A/D4*-Antagonist + CNS compound

interleukin-1 5-HT2A beta Antagonist + 5-HT2A (nitric converting cathepsin MAO-B D4-Antagonist+ Antagonist + MEDICAL Antag oxide) enzyme K re-uptake CNS D4 INDICATION onist NSAID: inhibitor inhibitor unknown inhibition Compound Antagonist

DISORDER WITH X X X X X ANUNDERLYING EMOTION DYSREGULATION NON-COGNITIVE MENTAL DISORDERS (excl. Pain Disorder) mood disorders X anxiety disorders X psychotic disorders X eating disorders X premenstrual syndrome X Somatoform disorders X (excluding Pain Disorder) factitious disorders X dissociative disorders X sexual and gender X identity disorders sleep disorders X adjustment disorders X impulse control X disorders