WO2012072665A1

WO2012072665A1 - Compositions comprising pipamperone and serotonin antagonist reuptake inhibitors

Info

Publication number: WO2012072665A1
Application number: PCT/EP2011/071350
Authority: WO
Inventors: Erik Buntinx
Original assignee: Pharmaneuroboost N.V.
Priority date: 2010-11-30
Filing date: 2011-11-30
Publication date: 2012-06-07

Abstract

The present invention relates to compositions comprising pipamperone and a serotonin antagonist/reuptake inhibitor (SARI), as well as the use of such compositions for the treatment of mood and anxiety disorders.

Description

COMPOSITIONS COMPRISING PIPAMPERONE AND SEROTONIN ANTAGONIST

REUPTAKE INHIBITORS

Technical field

The invention relates to the field of neuropsychiatry. More specifically, the invention relates to compositions comprising pipamperone and at least one serotonin antagonist reuptake inhibitor (SARI) and the use of such compositions for the treatment of mental disorders characterized by emotion dysregulation.

Background

Conventionally, mental disorders are divided into types based on criteria sets with defining features.

DSM-IV (American Psychiatric Association, (1993 - ISBN 0 - 89042 - 061 - 0)) is the in the art well-known gold standard of such a categorical classification. In DSM-IV, there is no assumption that each category of mental disorder is a completely discrete entity with absolute boundaries dividing it from other mental disorders or from no mental disorder. There is also no assumption that all individuals described as having the same mental disorder are alike in all important ways. Individuals sharing a diagnosis are likely to be heterogeneous even in regard to the defining features of the diagnosis. Thus, the categorical defined mental disorders mood and anxiety disorders are having an external and even internal variable co-incidence of symptoms concerning mood and anxiety.

In a dimensional system, clinical presentations are classified based on quantification of attributes, i.e. dysfunctions rather than the assignment to categories. This works best in describing phenomena, which are distributed continuously and which do not have clear boundaries. Emotion dysregulation is known as such an attribution or dysfunction that plays an important role in the development and course of mental disorders (Gross, J. J. & Munoz, R. F., 1995, Clinical Psychology: Science and Practice, 2, 151-164; Mennin, D.S., Heimberg, R. G., Turk, C. L. & Fresco, D. M., 2002, Clinical Psychology: Science and Practice, 9, 85-90; Linehan, M. M., 1993, New York, The Guilford Press; Gratz, K. L, Roemer, L, 2001 & 2004, Annual meeting of the Association for Advancement of Behavior Therapy, Nov. 2001 & Journal of Psychopathology and Behavioral Assessment, Vol. 26, No. 1, March 2004) besides behavioural and cognitive dysfunctions.

Finally, in the biological system, mental disorders are defined on other levels of abstraction than in the categorical and dimensional system. Structural pathology (e.g. amyloid plaques in Alzheimer Disease), etiology (e.g. HIV Dementia) and deviance from a physiological norm (e.g. reduced cerebral blood flow) are often used as indicative biological markers for a mental disorder. The underlying dysregulation of various neurotransmittor systems (glutaminergic, GABAergic, cholinergic, monoaminergic (nor- adrenergic, dopaminergic, serotonergic), etc.) is the in the art used model for the explanation of the biological determinants of the clinical presentation of mental disturbances.

Mood disorders include major depressive disorder, bipolar disorder (combining episodes of both mania and depression) and dysthymia. As a group, mood disorders are one of the most common mental illnesses in the general population. Approximately 8% of adults will experience major depression at some time in their lives, while approximately 1 % will experience bipolar disorder. Other studies have reported that between 3% and 6% of adults will experience dysthymia during their lifetime, and that between 0.6% and 1 % of adults will have a manic episode during their lifetime. Because of their high prevalence, economic cost, risk of suicide and loss of quality of life, mood disorders present a serious public health concern in society. Also, depression and mania cause significant distress and impairment in social, occupational, educational or other important areas of functioning. According to the World Health Organization (WHO), major depression is the fourth leading cause of disability adjusted life years (DALYs) in the world. Major depression is the leading cause of years of life lived with disability (YLD) and bipolar is the sixth leading cause. Social and economic effects of mood disorders include functional impairment, disability or lost work productivity, and increased use of health services.

Depression is a serious mood disorder which affects millions of people, while the number of people being diagnosed with depression has increased dramatically. There is no single known cause of depression. Rather, it likely results from a combination of genetic, biochemical, environmental, and psychological factors. Nevertheless, important neurotransmitters appear to be out of balance. In particular, serotonin signaling is affected in depressed patients. Hence, depression is treated with antidepressants which work to normalize neurotransmitters, notably serotonin and norepinephrine. Other antidepressants work on the neurotransmitter dopamine. Although it is found that these particular neurotransmitters are involved in regulating mood, it is uncertain of the exact ways in which they work.

Anxiety disorders are the most common of emotional disorders and affect more than 25 million Americans. Anxiety disorder is a persistent fear of social or performance situations that might involve exposure to unfamiliar people or possible scrutiny by others. Many forms and symptoms may include: overwhelming feelings of panic and fear, uncontrollable obsessive thoughts, painful, intrusive memories, recurring nightmares, and even physical symptoms such as feeling sick to your stomach, "butterflies" in your stomach, heart pounding, startling easily, and muscle tension. This condition, which often remains undetected and untreated, undermines a person's ability to become self-sufficient and impedes efforts to reduce welfare costs through return-to-work programs. Patients with this disorder commonly underperform educationally, have a lower probability of marrying, a lower economic status, and a higher probability of losing their job. The early onset of symptoms in adolescence interferes with the acquisition of social skills, resulting in social isolation. Patients with anxiety disorders are frequent users of the public health system. All these problems can be worsened if the anxiety disorder is accompanied by other mental disorders. Nevertheless, anxiety disorder is commonly under-diagnosed. The limitation of lives and the economic and social problems are always underestimated. An early diagnosis and treatment are key elements for lowering the social and economic burden of social anxiety disorder. Types of Anxiety Disorders include panic disorder, phobias, obsessive-compulsive disorer (OCD), posttraumatic stress disorder (PTSD) and generalized anxiety disorder (GAD). If left untreated, anxiety disorders can have severe consequences resulting in avoidance behavior which may create problems by conflicting with job requirements, family obligations or other basic activities of daily living. Moreover, many people who suffer from an untreated anxiety disorder are prone to other psychological disorders, such as depression, and they have a greater tendency to abuse alcohol and other drugs. Their relationships with family members, friends and coworkers may become very strained, while their job performance may falter.

Obsessions are upsetting and irrational thoughts which keep reoccurring. They cause great anxiety, which cannot be controlled through reasoning. Common obsessions include preoccupations with dirt or germs, nagging doubts, and a need to have things in a very particular order. To minimize these obsessions, many people with obsessive-compulsive disorder (OCD) engage in repeated behaviour, or compulsions. Examples include repeated hand washing, constant rechecking to satisfy doubts, and following rigid rules of order. Compulsive behaviour can be very disruptive to normal daily routines and social relationships.

Hence, because of their high prevalence, apart from the impact on the individual itself and his relation, mood and anxiety disorders have a major effect on economy. This effect is dual in nature - first, with the associated loss of productivity in the workplace due to absenteeism and diminished effectiveness; and second, with the high health care costs attributable to primary care visits, hospitalizations and medication. At the individual and family level, the loss of income and cost of medication create a strain on the family financial resources. Hence, mood and anxiety disorders have a major economic impact through associated health care costs as well as lost work productivity. Accordingly, there is a substantial need to diagnose and treat these disorders.

Mainstream treatment for mood and anxiety disorders consists of the prescription of antidepressants (for both mood and anxiety disorders) and anxiolytic agents (mainly for anxiety disorders). Many different types of antidepressants are currently on the market. The antidepressants can be classified according to their primary mode of action. Drugs belonging to classes including the serotonin reuptake inhibitors (SRIs, including SSRIs, SNRIs and SNDRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs) and SARIs, are among the most commonly prescribed antidepressants. Due to the specific action of each class of antidepressants, different benefits as well as different side effects are associated with the various classes. In general, all antidepressants influence to one extent or another various neural systems and pathways. In particular, antidepressants exert their therapeutic effect by influencing neurotransmission as well as neurotransmitters. Most prominently, antidepressants directly or indirectly modulate serotonergic, dopaminergic, adrenergic and glutaminergic systems. While it is believed that serotonergic modulation constitutes a main desired effect of antidepressants, modulation of the additional systems and pathways is thought to be of importance as well.

Modulation of each of the systems and pathways is achieved in different ways for the different classes of antidepressants. MAOIs, for instance, block the degradation of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine by inhibiting the enzyme monoamine oxidase, leading to increased concentrations of these neurotransmitters in the brain and an increase in neurotransmission. Other classes of antidepressants generally mediate neurotransmission by binding of the antidepressant to one or more of the cellular receptors for neurotransmitters which are involved in the respective neural pathways. Indeed, these classes of antidepressants can in fact be classified according to their receptor binding profile. For instance, the SRIs have the strongest affinity for the serotonin transporter (SERT). Binding of the antidepressant to SERT inhibits presynaptic serotonin reuptake and as a consequence leads to increased synaptic serotonin concentrations and an increase in neurotransmission.

As indicated above, while some antidepressants have a more narrow primary mode of action, generally, antidepressants are not exclusively specific for the intended targets, which may lead to off-target effects. In addition, even if reasonably specific, due to the complex interplay between various neural systems, including numerous feed-back mechanisms, most, if not all, antidepressants display a broad spectrum of physiological effects, including unintended and deleterious side effects. Commonly observed side effects for SRIs include for instance headache, nausea, insomnia, nervousness, agitation and sexual problems. Also the serotonin syndrome has been has been shown to result from the use of not only SRIs, but many types of antidepressants, including SARIs.

Apart from the side effects, clinical or real effectiveness of psychopharmaca is very rare via common pooping-out; many treatment-refractory patients and up to half of patients fail to attain remission (S. M. Stahl, Essential Psychopharmacology, Depression and Bipolar Disorders, 151, University Press; 2 edition (June 15, 2000); ISBN: 0521646154). Implications of not attaining remission for Mental Disorders are increased relapse rates, continuing functional impairment and increased suicide rate (S. M. Stahl, ibid). Clinical causes of not attaining remission by the Current Psychopharmacological Compounds are inadequate early treatment, underlying emotion dysregulation (affecting instability - hypersensitivity - hyperaesthesia - dissociative phenomena, etc.) and competitive antagonism.

SARIs (serotonin antagonist reuptake inhibitors) are a class of antidepressants which have binding affinities for various neurotransmitter receptors and transporters. SARIs have the strongest affinity for the 5-HT₂A serotonin receptor and act as an antagonist of this receptor. SARIs also have a strong affinity for the 5-HT_1A serotonin receptor and act as a partial agonist of this receptor. In addition, SARIs have a low to moderate affinity for SERT and act as an inhibitor of this transporter. Due to their demonstrated affinity for SERT, initially, it had been postulated that SARIs act in a similar fashion as SRIs by inhibiting SERT, thereby increasing synaptic serotonin concentration and neurotransmission. However, due to its manyfold lower binding affinity for SERT than for the 5-HT₂A and 5-HT_1A receptors, the clinical response of SARIs is dominated by 5-HT₂A receptor antagonism and 5-HT_1A receptors partial agonism, thereby clearly distinguishing the mode of action of SARIs from for instance the mode of action of SRIs. At low doses, SARIs do not display antidepressant activity, but rather function as hypnotics. Only at high doses, SARIs can function as antidepressants. However, adverse side effects of this class of antidepressants include in fact their hypnotic properties. It is believed that 5-HT₂A receptor antagonism plays an important role in these hypnotic effects. Moreover, SARIs also have moderate to strong affinity for the a1 , a2 and/or H1 receptors, which in conjunction with the effects on 5-HT₂A cumulatively exert hypnotic effects. Additional common side effects associated with SARIs include dizziness, lightheadedness, drowsiness, nausea and vomiting, nervousness, headache, dry mouth and blurred vision.

From the above, it is clear that the pharmacology, including drug target versatility and receptor binding profiles, as well as the multiple intertwined feedback mechanisms, makes the study of psychopharmaca in general, and antidepressants in particular, extremely complicated. Due to the, albeit partly overlapping, yet ultimately unique properties of each class of antidepressants, responses towards particular compounds is highly unpredictable, and extrapolation of pharmacological as well as physiological responses between different classes of antidepressants should be handled with great reservation. Combinations of different drugs, being it different types of antidepressants, and even more so combinations of antidepressants with drugs which are not antidepressants, should be approached with extreme caution.

While SARIs generally have a good safety profile and prompt relief of symptoms (Munozza, 2006, Current Medical Research and Opinions, 22: 1703-1713), for reasons of the above mentioned side effects of SARIs, these compounds are currently not often used as first line antidepressants. Rather, intolerability towards or ineffectiveness of other antidepressants may incite the use of SARIs. More often, SARIs are used as conjunctive therapy with other antidepressants, notably SRIs. In this respect, SARIs have been shown to function in augmenting SRI effectiveness.

Hence, there is a need for more efficient, selective and efficacious medicaments for treating mood and anxiety disorders.

Summary

The present inventor surprisingly found that the effects of SARIs may be further ameliorated when used in conjunction with a low dose of pipamperone. Accordingly, the present invention relates in particular to the subject-matter of the appended claims as presented herein.

The instruction leaflet from the manufacturer Janssen Cilag B.V details psychoses and the symptomatic treatment of serious forms of agitation and anxiety as the therapeutic indications for pipamperone. The leaflet warns against the use of pipamperone in depression. The recommended initial dose is 40 to 80 mg pipamperone a day. If necessary, it is recommended to increase the dose up to a maximum of 360 mg pipamperone per day. According to the present invention, pipamperon doses range between 0.1 and 20 mg. Due to this particularly low dose of pipamperone, the pharmacological properties, such as receptor binding profile, is not comparable anymore with the pharmacological properties at conventional doses. Indeed, whereas conventional doses for the treatment of psychosis aim amongst others at D2 dopamine receptor blockage, the instant low pipamperone doses are not capable of in vivo D2 receptor blockage. Hence, antipsychotic effects are lost. It is safe to say that low dose pipamperone in fact constitutes a different drug than conventional (or high) dose pipamperone.

WO 2005/053796 relates to low doses of antagonists of 5-HT2A and D4 receptors in order to augment the effects of these compounds in mental disorders, notably mood and axiety disorders. One of these antagonists is pipamperone, which is active in the range of 5-15 mg per day for a broad class of compounds, notably SRIs.

It is assumed that, for the most part, the effect of antidepressants ultimately depends on the activation of the 5-HT_1A receptor. Many antidepressant drugs achieve this goal by increasing serotonin concentrations, thereby indirectly leading to the activation of the 5- HT_1A receptor. SRIs, for example, block the serotonin transporter (SERT) and hence serotonin reuptake, thereby increasing synaptic serotonin concentrations. This increased serotonin concentration leads to an increased activation of the 5-HT_1A receptor, resulting in antidepressant activity.

For SARIs, given the fact that the affinity for SERT is manifold (up to a 100 fold) lower than the affinity for the 5-HT₂A and 5-HT_1A receptors, it has been postulated that the antidepressant mode of action of this class of antidepressants is mediated by the combined effects on the 5-HT₂A and 5-HT_1A receptors (Marek, Psychopharmacology, 1992, 109:2-11). In particular, SARIs are partial agonists of the 5-HT_1A receptor, thereby being directly linked to antidepressant activity. In addition, it is known that activation of the 5-HT_2A receptor can function to provide a negative feed-back mechanism towards the 5- HT_1A receptor. In this context, an increased serotonin concentration indiscriminately activates both the 5-HT_2A and 5-HT_1A receptors (as well as other serotonin receptors). While activation of the 5-HT_1A receptor initiates antidepressant activity, simultaneous activation of the 5-HT_2A receptor suppresses the 5-HT_1A receptor, thereby counteracting the antidepressant activity. As SARIs combine these two effects, antidepressant activity of these compounds has been attributed to the combined antagonistic and agonistic action on the 5-HT₂A and 5-HT_1A receptor, respectively. However, the strong affinity of SARIs for the 5-HT₂A receptor has also been associated with many of the side effects of these drugs, notably the hypnotic-associated side effects.

The present inventor has contraintuitively and surprisingly found that a low dose of pipamperone, which in itself, even at the claimed low dose, also has a very strong affinity for the 5-HT₂A receptor, can be combined with SARIs to provide a superior antidepressant effect, while at the same time, surprisingly, no concomitant increase in side effects is observed.

First, it is completely unexpected that combining pipamperone with an SARI would even lead to an improved antidepressant activity. Pipamperone has been assumed to exert its augmenting effect on SRIs by complementing the increased serotonin concentration, due to SERT inhibition by SRIs, with 5-HT₂A receptor antagonism, thereby counteracting the negative feedback of the 5-HT₂A receptor on the 5-HT_1A receptor. As SARIs already possess a potent 5-HT₂A receptor antagonism themselves, one would not have expected an additional effect of the combination with a second, i.e. pipamperone, 5-HT₂A receptor antagonist.

Second, as the side effects of SARIs have been attributed, among other by their 5-HT_2A receptor antagonism, one would have expected that combining these drugs with a second, i.e. pipamperone, 5-HT_2A receptor antagonist would only exacerbate these side effects.

Without wishing to be bound by theory, the inventor believes that the specific overall receptor binding profile of pipamperone may account for the observed effects. Indeed, besides being a potent 5-HT_2A receptor antagonist, pipamperone is also a potent D4 dopamine receptor antagonist. Numerous feedback mechanisms and interplays have been described between serotonergic and dopaminergic pathways. For instance, 5-HT_2A antagonism, besides giving the above described des-inhibition of the inhibitory effect of the 5-HT_2A receptor on the 5-HT_1A receptor stimulation by serotonin (S. M. Stahl, Newer Antidepressants and Mood Stabilizers, Essential Psychopharmacology, 265 , University Press; 2 edition (June 15, 2000); ISBN: 0521646154), also leads to des-inhibition of the inhibitory effect of the 5-HT_2A receptor on the dopamine release in the mesocortical systems (S. M. Stahl, ibid.). The importance for the dopamine system for depression is supported by several lines of evidence (Naranjo, Neuropyscholpharmacol. Biol. Psychiatry, 2001 ,25:781-823; Diehl, 1992, Compr. Psychiatry, 33:115-120). It is therefore tempting to speculate that the therapeutic action of serotonergic drugs is influenced by a functional interaction with the dopamine neurotransmitter system.

In a first aspect, the invention relates to a pharmaceutical composition comprising pipamperone in a dose between 0.1 and 20 mg (of the active ingredient) or a pharmaceutically acceptable salt thereof and at least one serotonin antagonist and reuptake inhibitor (SARI), or a pharmaceutically acceptable salt thereof, or a derivative thereof or an active metabolite thereof. In an embodiment, the composition comprises pipamperone in a dose between 5 and 15 mg. In an embodiment, said SARI in the composition is selected from the group consisting of trazodone, etoperidone, nefazodone, and lubazodone. Preferably said SARI is trazodone, or a pharmaceutically acceptable salt thereof, or a derivative thereof or an active metabolite thereof. In an embodiment, the dose of said SARI is between 20 and 600 mg (of the active ingredient), preferably between 20 and 400 mg. In a further embodiment, said pipamperone and said SARI are the sole pharmaceutically active ingredients in the composition. In another embodiment, said composition further comprises at least one pharmaceutically acceptable excipient.

In an embodiment, at least said SARI is formulated for extended release.

In another aspect, the invention relates to a composition as described herein, for use in treating a disorder characterized by an underlying emotion dysregulation. In an embodiment, said disorder is selected from the group consisting of mood disorders and/or anxiety disorders. In a further embodiment, said mood disorder is Major Depressive Disorder.

In an embodiment, the composition is to be administered daily. In another embodiment, the composition is to be divided for multiple administrations per day.

In one embodiment, pipamperone and said SARI are to be administered simultaneously or sequentially. In a further embodiment, said SARI is to be administered at least one day after the onset of administration of said pipamperone. Detailed description

Before the present method and products of the invention are described, it is to be understood that this invention is not limited to particular methods, components, products or combinations described, as such methods, components, products and combinations may, of course, vary. It is also to be understood that the terminology used herein is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

As used herein, the singular forms "a", "an", and "the" include both singular and plural referents unless the context clearly dictates otherwise.

The terms "comprising", "comprises" and "comprised of" as used herein are synonymous with "including", "includes" or "containing", "contains", and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. It will be appreciated that the terms "comprising", "comprises" and "comprised of" as used herein comprise the terms "consisting of", "consists" and "consists of".

The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints.

The term "about" or "approximately" as used herein when referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, is meant to encompass variations of +/-10% or less, preferably +1-5% or less, more preferably or less, and still more preferably +/-0.1 % or less of and from the specified value, insofar such variations are appropriate to perform in the disclosed invention. It is to be understood that the value to which the modifier "about" or "approximately" refers is itself also specifically, and preferably, disclosed.

Whereas the terms "one or more" or "at least one", such as one or more or at least one member(s) of a group of members, is clear per se, by means of further exemplification, the term encompasses inter alia a reference to any one of said members, or to any two or more of said members, such as, e.g., any≥3,≥4,≥5,≥6 or≥7 etc. of said members, and up to all said members.

All references cited in the present specification are hereby incorporated by reference in their entirety. In particular, the teachings of all references herein specifically referred to are incorporated by reference. Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions are included to better appreciate the teaching of the present invention.

In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments. Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art. For example, in the appended claims, any of the claimed embodiments can be used in any combination.

Depression and anxiety disorders can be treated with serotonin antagonists/reuptake inhibitors (SARIs). Unfortunately, however, these compounds can give rise to side effects in use, including sedation.

A problem to be solved by the present invention is thus the provision of a more efficient therapy and efficient, highly selective and efficacious medicaments for treating mental disorders, in particular depression and anxiety.

The present inventor surprisingly found that pipamperone at a dose between 0.1 and 20 mg/day in combination with SARIs, in particular trazodone, etoperidone, nefazodone, and lubazodone, has an improved effect in treating mood and anxiety disorders. Contrary to the findings of the present inventor, it was expected that pipamperone would on the one hand not have a beneficial effect in combining with SARIs, and on the other hand might even exacerbate the unwanted side effects of SARIs.

The present inventor surprisingly found that a simultaneous or foregoing treatment with pipamperone having a high selective 5-HT₂A and D4 receptor antagonist activity leads to a greater response towards SARIs. In particular, the present inventor surprisingly found that pipamperone at a dose ranging between 0.1 and 20 mg/day in combination with SARIs, has an improved effect in treating mood and anxiety disorders, by an increased D4 and 5-HT₂A receptor occupancy, while adverse effects are not increased or preferably absent.

The combination treatment and medicaments of the invention provides faster symptom resolution, less residual symptoms and/or more remission relative to a mono therapy with these compounds.

In a fist aspect, the invention relates to a pharmaceutical composition comprising pipamperone in a dose between 0.1 and 20 mg (of the active ingredient) or a pharmaceutically acceptable salt thereof and at least one serotonin antagonist and reuptake inhibitor (SARI), or a pharmaceutically acceptable salt thereof, or a derivative thereof or an active metabolite thereof. In an embodiment, said composition consists essentially of pipamperone in a dose between 0.1 and 20 mg (of the active ingredient) or a pharmaceutically acceptable salt thereof and at least one serotonin antagonist and reuptake inhibitor (SARI), or a pharmaceutically acceptable salt thereof, or a derivative thereof or an active metabolite thereof. In a further embodiment, said composition consists of pipamperone in a dose between 0.1 and 20 mg (of the active ingredient) or a pharmaceutically acceptable salt thereof and at least one serotonin antagonist and reuptake inhibitor (SARI), or a pharmaceutically acceptable salt thereof, or a derivative thereof or an active metabolite thereof.

As used herein, the term "consists essentially of" refers to a composition comprising only the referenced ingredients as (pharmaceutically) active compound. Accordingly, in an embodiment, the invention relates to a composition as described herein, wherein pipamperone in a dose between 0.1 and 20 mg (of the active ingredient) or a pharmaceutically acceptable salt thereof and at least one serotonin antagonist and reuptake inhibitor (SARI), or a pharmaceutically acceptable salt thereof, or a derivative thereof or an active metabolite thereof are the sole (pharmaceutically) active ingredients.

It is to be understood that "at least one" SARI includes 1 , 2, 3, 4, or even more SARI. Preferably the compositions as described herein comprise only one SARI. As used herein, the term "pharmaceutical composition" refers to a composition which can be used as a medecine. As such, a pharmaceutical composition is intended to be beneficial for the treatment of a particular disease or disorder. Therefore, a pharmaceutical composition is a non-toxic composition. It is to be understood that, while the composition may display unintended side effects when administered to a subject, such composition is nevertheless considered not to be toxic, due to the intended benefits attributed to the composition. A skilled person will appreciated that, occasionally, harmful side effects may occur, such as allergies towards one or more compounds within the composition. Such does not, however, preclude this composition as being generally (i.e. to the patient population as a whole) to be beneficial and non-toxic.

As used herein, the term "derivative" refers to a compound which is derived from another compound by chemical modification of said other compound. Preferably, said derivative has the same activity or substantially the same activity as the compound from which it is derived from.

As used herein, the term "active metabolite" refers to a catabolic breakdown product of a specific compound which still displays a pharmacological activity. Preferably, said metabolite has the same activity or substantially the same activity as the compound from which it is a metabolite of.

In a further aspect, the invention relates to a composition as described herein, for use in treating a disorder characterized by an underlying emotion dysregulation. In an embodiment, said disorder is selected from the group consisting of mood disorders and/or anxiety disorders. In a further embodiment, said mood disorder is Major Depressive Disorder.

In another aspect, the invention relates to the use of a composition as described herein, for treating a disorder characterized by an underlying emotion dysregulation. In an embodiment, said disorder is selected from the group consisting of mood disorders and/or anxiety disorders. In a further embodiment, said mood disorder is Major Depressive Disorder.

In yet another aspect, the invention relates to the use of a composition as described herein, for the manufacture of a medicament for treating a disorder characterized by an underlying emotion dysregulation. In an embodiment, said disorder is selected from the group consisting of mood disorders and/or anxiety disorders. In a further embodiment, said mood disorder is Major Depressive Disorder. In still another aspect, the invention relates to a method for treating a disorder characterized by an underlying emotion dysregulation, comprising administering a composition as described herein. In an embodiment, said disorder is selected from the group consisting of mood disorders and/or anxiety disorders. In a further embodiment, said mood disorder is Major Depressive Disorder.

Mood and anxiety disorders can be diagnosed using criteria found in the American Psychiatric Association's revised fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), and the WHO'S International Statistical Classification of Diseases and Related Health Problems (ICD-10). DSM-IV sets forth diagnostic criteria, descriptions and other information to guide the classification and diagnosis of mental disorders and is commonly used in the field of neuropsychiatry. It is for instance available on the internet under: http://www.behavenet.com/ capsules/disorders/ dsm4tr.htm.

The mood disorders grouped under the DSM-IV include major depressive disorder, dysthymic disorder, bipolar disorder, cyclothymic disorder, mood disorder due to a general medical condition and substance induced mood disorder. For each of these mood disorders there are specific criteria that a person's symptoms must meet in order to receive a diagnosis.

The anxiety disorders grouped under the DSM-IV include panic disorder, phobias, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD) and generalized anxiety disorder (GAD). For each of these anxiety disorders there are specific criteria that a person's symptoms must meet in order to receive a diagnosis.

The term "depression" according to the invention includes Major depressive disorder, Major depressive episode, Atypical depression, Melancholic depression, Psychotic depression, Depressive Disorder Not Otherwise Specified, Depression (mood), Postpartum depression, Dysthymia, Adjustment disorder with depressed mood, Seasonal affective disorder (SAD), all as known in the art.

Depression can be scored by e.g. the Hamilton Depression Rating Scale (HDRS or HAMD) (Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 196023:56-62) or the Montgomery-Asberg Depression Rating Scale (abbreviated MADRS). There is, however, a high degree of statistical correlation between scores on the two measures. The Clinical Global Impression (CGI) rating scales are commonly used measures of symptom severity, treatment response and the efficacy of treatments in treatment studies of patients with mental disorders. The CGI - Severity scale (CGI-S) is a 7-point scale which can be used by the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis.

The high selective affinity of pipamperone towards the 5-HT₂A receptor and the D4 receptor is reflected in the low dosage which is needed for the combination treatment with SARIs of mood or anxiety disorders.

Pipamperone is the conventional name given for the compound of the formula T-[3-(p- Fluorobenzoyl)propyl]-[1 ,4'-bipiperidine]-4'-carboxamide. Pipamperone is also the active ingredient of for instance the commercially available Dipiperon (Janssen, Cilag B.V).

According to the leaflet of the manufacturer, the therapeutic indications for pipamperone are psychoses and the symptomatic treatment of serious forms of agitation and anxiety only. Pipamperone is contraindicated for depression. For adults it is recommended to start with 40 to 80 mg a day. If necessary the dose may be increased to a maximum of 360 mg per day. In conventional pipamperone treatment, the active ingredient is available in tablets of 40 mg per tablet or in solutions of 2 mg per drop. Conventional usage of high doses ranging from 40 to 360 mg is prescribed. For instance, for children up to the age of 14, doses corresponding with 2 to 6 mg per kg body weight are conventionally prescribed.

In an embodiment, the compositions as described herein comprise pipamperone, or a pharmaceutically acceptable salt thereof, in a dose between (about) 0.1 and 20 mg per day, preferably between (about) 5 and 15 mg In a further embodiment, the compositions as described herein comprise pipamperone, or a pharmaceutically acceptable salt thereof, in a dose of (about) 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 , 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6,

1.7, 1.8, 1.9, 2, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1 , 3.2, 3.3, 3.4, 3.5, 3.6, 3.7,

3.8, 3.9, 4, 4.1 , 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1 , 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1 , 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1 , 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9,

8, 8.1 , 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1 , 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1 , 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11 , 1 1.1 , 1 1.2, 11.3, 11.4, 1 1.5, 1 1.6, 1 1.7, 1 1.8, 1 1.9, 12, 12.1 , 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13, 13.1 , 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14, 14.1 , 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15, 15.1 , 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16, 16.1 , 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17, 17.1 , 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18, 18.1 , 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19, 19.1 , 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, and 20 mg. It is to be understood that the listed doses and dose ranges of pipamperone are for daily administration. Accordingly, in an aspect, the daily dose of pipamperone in the compositions as described herein for the treatment of mood and anxiety disorders, such as depression is as listed above.

It will be appreciated by a person skilled in the art that pipamperone doses at the lower end of the dose range may be preferred for the treatment of mood and anxiety disorders in children and elderly patients. Accordingly, in an embodiment, doses up to about 15 mg, preferably up to about 10 mg, more preferable up to about 5 mg are to be administered daily to children or elderly patients for the treatment of mood and anxiety disorders.

It will be further appreciated by a person skilled in the art that doses, within the claimed dose range, may be varied for the treatment of mood and anxiety disorders depending on the body weight of the patient. Accordingly, in an embodiment, doses between (about) 0.05 and 0.25 mg per kg body weight are to be administered daily for the treatment of mood and anxiety disorders, such as for instance (about) 0.05, 0.06, 0.07, 0.08, 0.09, 0.1 , 0.1 1 , 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21 , 0.22, 0.23, 0.24, and 0.25 mg per kg body weight.

The term "serotonin antagonist reuptake inhibitor" or "SARI" as used herein refers to compounds which act by antagonizing serotonin receptors such as 5-HT₂A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. The term "SARI" does not exclude the effects of these compounds on any other compound, e.g. other neurotransmitters. In particular, SARI antidepressants include trazodone, etoperidone, nefazodone, and lubazodone, or a derivative thereof or an active metabolite thereof. Affinities (Kd in nM) of several SARIs for different receptors and transporters are listed in Table 1. The selected compounds act as antagonists at all receptors listed except at 5-HT_1A where they are partial agonists, and as inhibitors of all transporters listed.

Table 1

In an embodiment, the compositions as described herein comprise at least one SARI, preferably selected from the group consisting of trazodone, etoperidone, nefazodone, and lubazodone in a dose between (about) 20 mg and (about) 600 mg. In a further embodiment, the compositions as described herein comprise at least one SARI , preferably selected from the group consisting of trazodone, etoperidone, nefazodone, and lubazodone in a dose between (about) 20 mg and (about) 400 mg. In an embodiment, the dose of SARI is (about) 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 1 10, 1 15, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, or 600 mg.

It is to be understood that the listed doses and dose ranges of SARI are for daily administration. Accordingly, in an aspect, the daily dose of SARI in the compositions as described herein for the treatment of mood and anxiety disorders, such as depression is as listed above.

If the composition as described herein comprises more than one SARI , the dose of each SARI can be as listed above. More preferably, f the composition as described herein comprises more than one SARI , the total dose SARI added up is as listed above.

It will be appreciated by a person skilled in the art that SARI doses at the lower end of the dose range may be preferred for the treatment of mood and anxiety disorders in children and elderly patients.

It will be further appreciated by a person skilled in the art that doses, within the claimed dose range, may be varied for the treatment of mood and anxiety disorders depending on the body weight of the patient. Accordingly, in an embodiment, doses between (about) 0.25 and 10 mg per kg body weight are to be administered daily for the treatment of mood and anxiety disorders, such as for instance (about) 0.25, 0.5, 0.75, 1, 1 .25, 1.5, 1 .75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75, 10 mg per kg body weight.

Trazodone (l UPAC name 2-(3-[4-(3-chlorophenyl)piperazin-1 -yl]propyl)-[1 ,2,4]triazolo[4,3- a]pyridin-3(2/-/)-one) is marketed under the names Desyrel, Oleptro, Beneficat, Deprax, Desirel, Molipaxin, Thombran, Trazorel, Trialodine, Trittico and Mesyrel. Trazodone was originally developed by Angelini research laboratories (US3381009, incorporated herein by reference in its entirety). In a preferred embodiment, the present invention relates to compositions comprising pipamperone in the claimed dose range and trazodone or a pharmaceutically acceptable salt thereof, or a derivative thereof, or an active metabolite thereof. It will be appreciated by the skilled person that combinations of pipamperone with any of the marketed trazodone formulations are specific embodiments of the present invention.

Preferred daily trazodone doses, or doses of pharmaceutically acceptable salts thereof or doses of derivatives or active metabolites thereof, according to an embodiment are between 20 and 600 mg, such as between 20 and 500 mg, between 20 and 400 mg, preferably between 20 and 300 mg, more preferably between 20 and 200 mg, even more preferable between 20 and 150 mg, most preferably between 20 and 100 mg. It is to be understood that these doses are unitary doses, and may be divided over several fractional doses per day. In an embodiment, the dose is between 0.5 and 5 mg/kg body weight, such as 0.5, 1 , 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5 mg/kg body weight. In an embodiment, daily trazodone doses, or doses of pharmaceutically acceptable salts thereof or doses of derivatives or active metabolites thereof, are between 100 and 600 mg, such as between 100 and 500, between 100 and 400, between 100 and 300, between 100 and 200, between 150 and 600, between 150 and 500, between 150 and 400, between 150 and 300, between 150 and 200, between 200 and 600, between 200 and 500, between 200 and 400, or between 200 and 300 mg.

In an embodiment, derivatives of trazodone can be used. Preferred derivatives have Formula I.

Wherein R is hydrogen or methyl; and wherein R' is a member selected from the group consisting of hydrogen, lower alkyl having 1 to 4 carbon atoms, lower alkoxy having 1 to 4 carbon atoms, and halogen. In an embodiment, said derivative is a pharmaceutically acceptable salt of a compound with Formula I, preferably a salt with an organic or inorganic acid.

Additional preferred trazodone derivatives are disclosed in WO9314091 , which is incorporated herein by reference in its entirety. The preferred derivatives have Formula II.

Wherein only one of R, R', R", and R'" is a lower alkyl having 1 to 3 carbon atoms. In an embodiment, said derivative is a pharmaceutically acceptable salt of a compound with Formula II, preferably a salt with an organic or inorganic acid. A person skilled in the art will appreciate that compounds having a combination of Formula I and II are also preferred compounds in embodiments according to the invention.

Nefazodone (lUPAC name 1-(3-[4-(3-chlorophenyl)piperazin-1-yl]propyl)-3-ethyl-4-(2- phenoxyethyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one) is marketed under the names Serzone and Nefadar. Nefazodone was originally developed by Mead Johnson & Company (US4338317, incorporated herein by reference in its entirety). In a preferred embodiment, the present invention relates to compositions comprising pipamperone in the claimed dose range and trazodone or a pharmaceutically acceptable salt thereof, or a derivative thereof, or an active metabolite thereof. It will be appreciated by the skilled person that combinations of pipamperone with any of the marketed nefazodone formulations are specific embodiments of the present invention.

Preferred daily nafazodone doses, or doses of pharmaceutically acceptable salts thereof or doses of derivatives or active metabolites thereof, according to an embodiment are between 20 and 600 mg, such as between 20 and 500 mg, between 20 and 400 mg, preferably between 20 and 300 mg, more preferably between 20 and 200 mg, even more preferable between 20 and 150 mg, most preferably between 20 and 100 mg. It is to be understood that these doses are unitary doses, and may be divided over several fractional doses per day. In an embodiment, the dose is between 0.5 and 5 mg/kg body weight, such as 0.5, 1 , 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 mg/kg body weight. In an embodiment, daily trazodone doses, or doses of pharmaceutically acceptable salts thereof or doses of derivatives or active metabolites thereof, are between 100 and 600 mg, such as between 100 and 500, between 100 and 400, between 100 and 300, between 100 and 200, between 150 and 600, between 150 and 500, between 150 and 400, between 150 and 300, between 150 and 200, between 200 and 600, between 200 and 500, between 200 and 400, or between 200 and 300 mg.

In an embodiment, derivatives of trazodone can be used. Preferred derivatives have Formula III.

Wherein R is halogen. In an embodiment, said derivative is a pharmaceutically acceptable salt of a compound with Formula III, preferably a salt with an organic or inorganic acid.

Additional preferred nefazodone derivatives are disclosed in US4613600, WO0061 128, and WO0061129 relating respectively to hydroxynefazodone, the stereoisomer R- hydroxynefazodone, and the stereoisomer S-hydroxynefazodone respectively, the content of which is incorporated herein by reference in its entirety. Hydroxynefazodone has Formula IV

In an embodiment, (R-)hydroxynefazodone is a pharmaceutically acceptable salt of a compound with Formula IV, preferably a salt with an organic or inorganic acid. A person skilled in the art will appreciate that compounds having a combination of Formula III and IV are also preferred compounds in embodiments according to the invention.

Etoperidone (lUPAC name 2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-4,5-diethyl-1 ,2,4- triazol-3-one) is marketed under the name Axiomin, Depracer, Etonin, Etoran, Staff, and Tropene. Etoperidone is also known as clopradone and thozalinone. Etoperidone was originally developed by Angelini research laboratories (US3857845, incorporated herein by reference in its entirety). In a preferred embodiment, the present invention relates to compositions comprising pipamperone in the claimed dose range and etoperidone or a pharmaceutically acceptable salt thereof, or a derivative thereof, or an active metabolite thereof. It will be appreciated by the skilled person that combinations of pipamperone with any of the marketed etoperidone formulations are specific embodiments of the present invention. Preferred daily etoperidone doses, or doses of pharmaceutically acceptable salts thereof or doses of derivatives or active metabolites thereof, according to an embodiment are between 20 and 600 mg, such as between 20 and 500 mg, between 20 and 400 mg, preferably between 20 and 300 mg, more preferably between 20 and 200 mg, even more preferable between 20 and 150 mg, most preferably between 20 and 100 mg. It is to be understood that these doses are unitary doses, and may be divided over several fractional doses per day. In an embodiment, the dose is between 0.5 and 5 mg/kg body weight, such as 0.5, 1 , 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 mg/kg body weight. In an embodiment, daily etoperidone doses, or doses of pharmaceutically acceptable salts thereof or doses of derivatives or active metabolites thereof, are between 100 and 600 mg, such as between 100 and 500, between 100 and 400, between 100 and 300, between 100 and 200, between 150 and 600, between 150 and 500, between 150 and 400, between 150 and 300, between 150 and 200, between 200 and 600, between 200 and 500, between 200 and 400, or between 200 and 300 mg.

Lubazodone (lUPAC name (2S)-2-[(7-fluoro-2,3-dihydro-1 H-inden-4-yl)oxymethyl]- morpholine) is also known as YM-992, YM-35,995. In a preferred embodiment, the present invention relates to compositions comprising pipamperone in the claimed dose range and lubazodone or a pharmaceutically acceptable salt thereof, or a derivative thereof, or an active metabolite thereof.

Preferred daily lubazodone doses, or doses of pharmaceutically acceptable salts thereof or doses of derivatives or active metabolites thereof, according to an embodiment are between 20 and 600 mg, such as between 20 and 500 mg, between 20 and 400 mg, preferably between 20 and 300 mg, more preferably between 20 and 200 mg, even more preferable between 20 and 150 mg, most preferably between 20 and 100 mg. It is to be understood that these doses are unitary doses, and may be divided over several fractional doses per day. In an embodiment, the dose is between 0.5 and 5 mg/kg body weight, such as 0.5, 1 , 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 mg/kg body weight. In an embodiment, daily lubazodone doses, or doses of pharmaceutically acceptable salts thereof or doses of derivatives or active metabolites thereof, are between 100 and 600 mg, such as between 100 and 500, between 100 and 400, between 100 and 300, between 100 and 200, between 150 and 600, between 150 and 500, between 150 and 400, between 150 and 300, between 150 and 200, between 200 and 600, between 200 and 500, between 200 and 400, or between 200 and 300 mg. In an embodiment, derivatives of lubazodone can be used. Preferred derivatives have Formula V or VI (a levorotary optical isomer of V).

Wherein R and R"may be the same or different, each represent hydrogen or a lower alkyl group; R' represents a halogen atom; the dotted line indicates an optional double bond. In an embodiment, said derivative is a pharmaceutically acceptable salt of a compound with Formula V or VI, preferably a salt with an organic or inorganic acid.

In an embodiment, the dose of the SARIs as described herein for treating patients with mental disorders may be decreased to about 10 - 90% of the conventional dose, preferably to about 20 - 80%, or 30 - 70%, or 40 - 60% or to about 50% of the conventional dose. Even if the administered dose of the SARI is decreased in the combination therapy, the therapeutic effect may be sustained or ameliorated relative to the conventional dose. The danger of side effects of a treatment with SARIs, can be decreased or minimized in the combination therapy of the invention. In this regard, the term conventional dose refers to the dose used contemporaneously for SARIs, in particular trazodone, etoperidone, nefazodone, and lubazodone, for the treatment of mood disorders and anxiety disorders, for instance, according to the supplier's or physician's description.

The terms "treatment", "treating", and the like, as used herein include amelioration or elimination of a developed mental disease or condition, in particular depression, once it has been established or alleviation of the characteristic symptoms of such disease or condition. As used herein these terms also encompass, depending on the condition of the patient, preventing the onset of depression or of symptoms associated with depression, including reducing the severity of depression or symptoms associated therewith prior to affliction with said depression. Such prevention or reduction prior to affliction refers to administration of the compound or composition of the invention to a patient that is not at the time of administration afflicted with depression. "Preventing" also encompasses preventing the recurrence or relapse-prevention of depression or of symptoms associated therewith, for instance after a period of improvement. It should be clear that mental conditions, e.g. depression, may be responsible for physical complaints. In this respect, the term "treating" also includes prevention of a physical disease or condition or amelioration or elimination of the developed physical disease or condition once it has been established or alleviation of the characteristic symptoms of such conditions.

As used herein, the term "medicament" also encompasses the terms "drug", "therapeutic", "potion" or other terms which are used in the field of medicine to indicate a preparation with therapeutic or prophylactic effect.

According to a further embodiment, the invention relates to compositions of pipamperone for use in treating mood disorders or anxiety disorders, and in particular depression whereby pipamperone is administered simultaneously with or sequential to said SARIs, in particular trazodone, etoperidone, nefazodone, and lubazodone, to augment the therapeutic effect of said SARIs in the treatment of mood disorders and anxiety disorders, and in particular depression, or to provide a faster onset of the therapeutic effect of said SARIs in the treatment of said mood disorders and anxiety disorders, and in particular depression.

In an embodiment, when pipamperone is administered prior to the SARIs as disclosed herein, pipamperone is administered at least during 1 day prior to the onset of said SARI administration. Preferably, pipamperone is administered for at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 days prior to the administration of said SARI. Preferably, pipamperone is administered for at least 2, 3, 4 or 5 weeks prior to the administration of said SARI.

In another embodiment, pipamperone and the SARIs as disclosed herein are administered within 24 hours, e.g. on the same day, even more preferably within 16 hours, or even more preferably within 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 hour, or even less. In a further embodiment, pipamperone is administered at the same time or substantially the same time as the SARI as disclosed herein.

Pipamperone and SARIs are preferably administered once a day. In a further embodiment, the compounds are administered 2, or 3 or even 4 times a day. It will be understood that, apart from daily doses, the compounds can be administered by other schedules. For instance, the present invention also contemplates depot injection, controlled release, extended release or slow release formulations, in which a long acting form of the active compound is injected into the body, such as the muscles. From there the active compound slowly enters the rest of the body, so one injection can last from 1 to 4 weeks or even multiple months. Other form of dosage administrations relate to "once-a- week" pills, in which the ingredient is slowly released over a period of a week, and slow- release patches, e.g. a CDS (Continuous Delivery System), or Once-a-Day Transdermal Patches. In an embodiment, at least the SARI, optionally also pipamperone are formulated as a controlled release composition, a slow release composition or and extended release composition. In an embodiment the SARI, preferably trazodone, or a pharmaceutically acceptable salt thereof, or a derivative thereof or an active metabolite thereof and optionally also pipamperone are formulated for once a day administration as extended release. Suitable (preferred) formulations are disclosed in WO2007048219 (preferably for trazodone), WO2007048220 (preferably for trazodone), US6607748 (preferably for trazodone), US7829120 (preferably for trazodone), and US6143325 (preferably for nefazodone) the content of which is incorporated herein in its entirety.

It will be understood that the total dose of pipamperone per day of any dosage regime is as described above, e.g. from about 0.1 mg per day to about 20 mg pipamperone per day. In the present invention, pipamperone and SARIs, may be present a single composition or in separate compositions. The compositions according to the invention may be pharmaceutical compositions or formulations. If present in separate compositions, pipamperone and the SARIs may be administered simultaneously of sequentially.

In an embodiment, when pipamperone is administered simultaneously with or sequential to the SARIs as disclosed herein, said pipamperone and said SARI are administered in separate pharmaceutical compositions or formulations. Said separate pharmaceutical compositions or formulations of either pipamperone or SARI can be individually packed. Preferably, said separate pharmaceutical compositions or formulations are packed together, i.e. combined preparations, such as, for instance, in one box, on one strip, e.g. blister strip, etc. Said separate pharmaceutical compositions or formulations are preferred in adjusting individual doses of either or both compounds, within the ranges of the invention. Accordingly, the invention relates to combined preparations comprising a pharmaceutical composition comprising pipamperone, and a pharmaceutical composition comprising a SARI as defined herein, for simultaneous, separate or sequential use for treating a mood disorder or anxiety disorder, wherein said pipamperone is to be administered to a patient in a daily dose ranging between 0.1 and 20 mg of the active ingredient.

When pipamperone is administered simultaneously with said SARI as disclosed herein, said pipamperone and said SARI, e.g. the active ingredients thereof, are administered in separate pharmaceutical compositions or formulations, or in pharmaceutical compositions or formulations comprising both elements, such as, for instance, combination pharmaceutical compositions or combination formulations. Preferably, said combination is a pill, powder or solution comprising both pipamperone and said SARI at the doses of the invention, for ease in administration and management.

It has been found that the low dose pipamperone, or a pharmaceutically acceptable salt thereof, augments the therapeutic effect of and/or provides a faster onset of SARIs, in particular trazodone, etoperidone, nefazodone, and lubazodone, or a pharmaceutically acceptable salt thereof, or a derivative thereof or an active metabolite thereof in the treatment of mood disorders, such as depression, or anxiety disorders. It is further demonstrated that the combination treatment of the present invention provides at least a similar therapeutic effect with lower doses of SARIs as described herein, relative to the conventional doses of said SARIs.

The amount of pipamperone required to produce the efficacious effect will, of course, vary and is ultimately at the discretion of the medical practitioner. The factors to be considered include the route of administration and nature of the formulation, the patient's body weight, age and general condition and the nature and severity of the disease to be treated.

More commonly these days, pharmaceutical formulations are prescribed to the patient in "patient packs" containing the whole course of treatment in a single package, usually a blister pack. Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient's supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in traditional prescriptions. The inclusion of a package insert has been shown to improve the patient's compliance with the physician's instructions.

It will be understood that the administration of the combination of the invention by means of a single patient pack, or patient packs of each formulation, with a package insert directing the patient to the correct use of the invention is a desirable additional feature of this invention. According to a further aspect of the invention, there is provided a patient pack comprising at least one active ingredient of the combination of the invention and an information insert containing directions on the use of the combination of the invention.

According to another aspect the invention provides a double pack comprising in association for separate administration of either pipamperone or a SARI as disclosed herein.

The compounds according to the invention may be chemical or biological in nature, or may be chemically synthesised.

In this invention, the term "antagonist" refers to an interaction between chemicals in which one partially or completely inhibits the effect of the other, in particular agents having high affinity for a given receptor, but which do not activate this receptor. In this invention, the term "inverse agonist" refers to a ligand which produces an effect opposite to that of the agonist by occupying the same receptor. In this invention, the term "agonist" relates to an agent which both binds to a receptor and has an intrinsic effect. In this invention, the term "partial agonist" relates to an agent with lower intrinsic activity than a full agonist, and which produces a lower maximum effect.

The term "active metabolite" as used herein relates to a therapeutically active compound produced by the metabolism of a parent drug. Drugs administered to treat diseases are usually transformed (metabolized) within the body into a variety of related chemical forms (metabolites), some of which may have therapeutic activity (an active metabolite). A particularly preferred active metabolite of the SARIs as disclosed herein in mCPP (meta- Chlorophenylpiperazine; lUPAC name 1-(3-chlorophenyl)piperazine). mCPP is a common active metabolite of trazodone, nefazodone and etoperidone, and is a non-selective serotonin receptor agonist and serotonin releasing agent. It has been suggested that it may play a role in for instance trazodone's therapeutic benefits.

The present invention also encompasses compositions comprising pipamperone and SARIs, in particular trazodone, etoperidone, nefazodone, and lubazodone, administered in the form of a pharmaceutically acceptable salt in admixture with a suitable pharmaceutically acceptable excipient.

To prepare the pharmaceutical compositions, comprising pipamperone and SARIs, in particular trazodone, etoperidone, nefazodone, and lubazodone, an effective amount of the active ingredients, in acid or base addition salt form or base form, is combined in admixture with a pharmaceutically acceptable carrier, which can take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, for administration orally, nasal, rectally, percutaneously, transdermal^, by parenteral, intramuscular, intravascular injection or intrathecal administration. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.

The pharmaceutical compounds for treatment are intended for parenteral, topical, oral or local administration and generally comprise a pharmaceutically acceptable carrier and an amount of the active ingredient sufficient to reverse or prevent the bad effects of mental disorders. The carrier may be any of those conventionally used and is limited only by chemico-physical considerations, such as solubility and lack of reactivity with the compound, and by the route of administration.

Preferably, the compounds of the invention are provided as a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable acid addition salts for use in the present inventive pharmaceutical composition include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, p-toluenesulphonic acids, and arylsulphonic, for example. The present invention relates specifically to pipamperone and the use thereof, characterised in that said pipamperone is pipamperone dihydrochloride or pipamperone acetate. A preferred salt of the SARIs according to an embodiment of the invention is a hydrochloric acid salt. Accordingly, in a preferred embodiment, trazodone, etoperidone, nefazodone, and lubazodone is provided in the compositions according to the invention as trazodone, etoperidone, nefazodone, and lubazodone hydrochloride. Trazodone hydrochloride is disclosed in EP1108722 and WO2009019133, the content of which are incorporated herein by reference in its entirety. Nefazodone hydrochloride is disclosed in US6448404 , the content of which are incorporated herein by reference in its entirety. Another preferred salt of the SARIs according to an embodiment of the invention is a methane sulphonate salt. Accordingly, in a preferred embodiment, trazodone, etoperidone, nefazodone, and lubazodone is provided in the compositions according to the invention as trazodone, etoperidone, nefazodone, and lubazodone methane sulphonate. Nefazodone methane sulphonate is disclosed in US6034085, the content of which are incorporated herein by reference in its entirety. This salt of nefazodone is particularly useful in extended release formulations.

The pharmaceutically acceptable excipients described herein, for example, vehicles, adjuvants, carriers or diluents, are well-known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one that is chemically inert to the active compounds and one that has no detrimental side effects or toxicity under the conditions of use.

The following formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intramuscular, interperitoneal, rectal, and vaginal administration are merely exemplary and are in no way limiting. Overall, the requirements for effective pharmaceutical carriers for parenteral compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J.B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238-250, (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986). Topical formulations, including those that are useful for transdermal drug release, are well-known to those of skill in the art and are suitable in the context of the present invention for application to skin. Particularly preferred transdermal formulations for the SARIs as disclosed herein, including trazodone, etoperidone, nefazodone, and lubazodone, preferably trazodone or nefazodone, are disclosed in US6290986 and W0991 1208, the content of which ins incorporated herein by reference in its entirety.

Formulations, comprising pipamperone and SARIs, in particular trazodone, etoperidone, nefazodone, and lubazodone, suitable for oral administration require extra considerations considering the nature of the compounds and the possible breakdown thereof if such compounds are administered orally without protecting them from the digestive secretions of the gastrointestinal tract. Such a formulation can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions. Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Suitable (preferred) liquid formulations are disclosed in WO2009016069, the content of which is incorporated herein in its entirety. Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the art.

The compounds of the present invention, i.e. pipamperone and SARIs, in particular trazodone, etoperidone, nefazodone, and lubazodone, in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. For aerosol administration, the compounds are preferably supplied in finely divided form along with a surfactant and propellant. Typical percentages of compounds are 0.01 %-20% by weight, preferably 1 %-10%. The surfactant must, of course, be nontoxic, and preferably soluble in the propellant. Representative of such agents are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride. Mixed esters, such as mixed or natural glycerides may be employed. The surfactant may constitute 0.1 %-20% by weight of the compounds, preferably 0.25-5%. The balance of the compounds is ordinarily propellant. A carrier can also be included as desired, e.g., lecithin for intranasal delivery. These aerosol formulations can be placed into acceptable pressurized propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer. Such spray formulations may be used to spray mucosa. It should be clear that the compounds and compositions described herein are useful for treating any patient in need thereof, in particular humans.

Patients receiving antidepressant monotherapy may be or become partially or totally resistant to treatment in 10 to 30 percent of cases. "Pooping-out" can occur with any conventional antidepressant. Relapse or recurrence of depression while still taking medication (i.e., breakthrough) can also occur. While there is no definitive answer as to why this happens, it may be a case of the patient developing tolerance to the drug. The most commonly strategies used to deal with this problem include augmentation with a second drug, raising the dose or switching to another drug entirely.

A change from one antidepressant to another in the same or different class has not produced impressive response rates among depressed patients. If drug-switching is chosen as the method of therapy, patients should be closely monitored for possible drug interactions or other adverse effects. This is particularly true if the half-life of the first agent is quite long (e.g., fluoxetine [Prozac]) and another drug is begun before a prudent "wash- out" period has occurred. This situation may sometimes result in serotonin syndrome (toxic levels of central nervous system serotonin that result in hyperalertness, agitation, confusion, restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, tremor and, possibly, death).

The present inventors found that pipamperone in combination with a SARI as disclosed herein, also show an improved effect on treatment refractory patients with mood disorders or anxiety disorders. Because of high specific binding affinity, pipamperone can be used at low doses. At these low doses, adverse effects are minimized and/or precluded (see e.g. WO2005053796, which is herein incorporated by reference in its entirety).

Accordingly, the present invention relates to the use as described herein, characterised in that the pharmaceutical composition is for treatment of patients who have failed to respond to initial treatment with an antidepressant and/or anxiolytic agent, including a SARI or SRI. More in particular, the present invention relates to compositions as described above, characterised in that the pharmaceutical composition is for treatment of patients with major depression disorder who have failed to respond to initial treatment with an antidepressant or anxiolytic agent, including a SARI or SRI. Accordingly, the present invention relates to the compositions as described herein, characterised in that the pharmaceutical composition is for treatment of treatment refractory patients to an antidepressant or anxiolytic agent, including a SARI or SRI. More in particular, the present invention relates to the compositions as described herein, characterised in that the pharmaceutical composition is for treatment of major depression in treatment refractory patients to an antidepressant or anxiolytic agent, including a SARI or SRI.

The term "treatment refractory" patient is used as common in the art, such as, for instance, as understood by the clinician or physician monitoring and/or treating a patient. This term includes patients who have failed to respond to initial treatment, patients who are partially or totally resistant to treatment, patients with recurrent mood or anxiety disorder, and patients pooping-out. Patients who have failed to respond to initial treatment, include patients not ameliorating after for instance 2 weeks of treatment, as diagnosed by criteria described above.

Mood and anxiety disorders, in particular depression, have been described to be treatable with compounds having a high selective affinity for the 5-HT2A and D4 receptor, for instance pipamperone, in a combination with serotonin re-uptake inhibitors (SRIs), including selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenalin dopamine reuptake inhibitors (SNDRIs ) and serotonin noradrenalin reuptake inhibitors (SNRIs), as disclosed in WO2005053796. According to the present invention, mood and/or anxiety disorders can be treated with compositions comprising pipamperone and SARIs.

Accordingly, in an aspect, the invention also relates to a composition as described herein, further comprising one or more SRI. In a further aspect, the present invention relates to a composition as described herein, further comprising an at least one SRI, for use in treating a disorder characterized by an underlying emotion dysregulation. In an embodiment, said disorder is selected from the group consisting of mood disorders and/or anxiety disorders. In a further embodiment, said mood disorder is Major Depressive Disorder.

In another aspect, the invention relates to the use of a composition as described herein, further comprising at least one SRI, for treating a disorder characterized by an underlying emotion dysregulation. In an embodiment, said disorder is selected from the group consisting of mood disorders and/or anxiety disorders. In a further embodiment, said mood disorder is Major Depressive Disorder.

In yet another aspect, the invention relates to the use of a composition as described herein, further comprising at least one SRI, for the manufacture of a medicament for treating a disorder characterized by an underlying emotion dysregulation. In an embodiment, said disorder is selected from the group consisting of mood disorders and/or anxiety disorders. In a further embodiment, said mood disorder is Major Depressive Disorder.

In still another aspect, the invention relates to a method for treating a disorder characterized by an underlying emotion dysregulation, comprising administering a composition as described herein, further comprising at least one SRI. In an embodiment, said disorder is selected from the group consisting of mood disorders and/or anxiety disorders. In a further embodiment, said mood disorder is Major Depressive Disorder.

In an embodiment, said SRI is an SSRI compound selected from the group consisting of citalopram, escitalopram, YM 992, VPI-013 (also known as OPC-14523), sertraline, paroxetine, LY 214.281 , LU AA 21-004, Lu 35-138, litoxetine, ifoxetine, fluvoxamine (controlled release formulation), fluvoxamine, fluoxetine, femoxetine, EMD 68843, cyanodothepine, cericlamine, ademethionine (preferably s-adenosylmethionine), milnacipran, venlafaxine, duloxetine and desvenlafaxine or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof. Even more preferably, said SSRI compound is chosen from the group consisting of citalopram, escitalopram, litoxetine and fluvoxamine (controlled release formulation), or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof.

More preferably, said SSRI compound is citalopram and is to be administered in a daily dose ranging between 5 and 60 mg or between 20 and 40 mg of the active ingredient, such as 5, 7.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 mg; said SSRI compound is escitalopram and is to be administered in a daily dose ranging between 5 and 50 mg or between 12.5 and 25 mg of the active ingredient, such as 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 30, 35, 40, 45 or 50 mg; said SSRI compound is paroxetine and is to be administered in a daily dose ranging between 20 and 75 mg or between 25 and 60 mg of the active ingredient, such as 12.5, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or 75 mg; said SSRI compound is fluoxetine and is to be administered in a daily dose ranging between 20 and 60 mg or between 30 and 50 of the active ingredient, such as 20, 25, 30, 35, 40, 45, 50, 55 or 60 mg; said SSRI compound is fluvoxamine and is to be administered in a daily dose ranging between 50 and 300 mg or 100 and 200 mg of the active ingredient, such as 50, 75, 100, 150, 200, 250 or 300 mg; said SSRI compound is sertraline and is to be administered in a daily dose ranging between 25 and 300 mg or between 50 and 150 mg of the active ingredient, such as 25, 50, 75, 100, 150, 175, 200, 225, 250, 275 or 300 mg; said SSRI compound is fluvoxamine (controlled release formulation) and is to be administered in a daily dose ranging between 100 and 300 mg or between 150 and 200 mg of the active ingredient, such as 100, 150, 200, 250 or 300 mg; said SSRI compound is milnacipran and is to be administered in a daily dose ranging between 50 and 200 mg of the active ingredient, such as 50, 75, 100, 125, 150, 175 or 200 mg; said SSRI compound is venlafaxine and is to be administered in a daily dose ranging between 75 and 300 mg of the active ingredient, such as 75, 100, 125, 150, 175, 200, 225, 250, 275 or 300 mg; said SSRI compound is duloxetine and is to be administered in a daily dose ranging between 40 and 120 mg of the active ingredient, such as 40, 45, 50, 55, 60, 70, 80, 90, 100, 110 or 120 mg, and/or said SSRI compound is desvenlafaxine and is to be administered in a daily dose ranging between 50 and 250 mg of the active ingredient, such as 50, 75, 100, 125, 150, 175, 200, 225 or 250 mg. Accordingly, in an aspect, the invention relates to a composition as described herein, further comprising an SSRI in a unitary dose as indicated above. It is to be understood that these doses are unitary doses, and may be divided over several fractional doses per day.

According to the most preferred embodiment, the SRI is citalopram (lUPAC name (f?S)-1- (3-dimethylaminopropyl)-1-(4-fluorofenyl)- 1 ,3-dihydroisobenzo- furaan-5-carbonitril) or its S-entantiomer escitalopram, or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof.

In a further embodiment, said SRI is an SNRI compound selected from the group consisting of venlafaxine, tomoxetine, tandamine, talsupram, talopram, milnacipran, LY 113.821 , duloxetine, desvenlafaxine and amoxapine, or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof. Even more preferably, said SNRI compound is chosen from the group consisting of venlafaxine, tomoxetine, milnacipran, duloxetine and desvenlafaxine, or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof.

More preferably, said SNRI compound is milnacipran and is to be administered in a daily dose ranging between 50 and 200 mg of the active ingredient; said SNRI compound is amoxapine and is to be administered in a daily dose ranging between 100 and 600 mg of the active ingredient, such as 100, 150, 200, 250, 300, 350, 400, 450, 500, 550 or 600 mg; said SNRI compound is venlafaxine and is to be administered in a daily dose ranging between 75 and 300 mg of the active ingredient; said SNRI compound is duloxetine and is to be administered in a daily dose ranging between 40 and 120 mg of the active ingredient; said SNRI compound is tomoxetine and is to be administered in a daily dose ranging between 0.475 and 3.8 mg/kg body weight of the active ingredient, such as 0.475, 0.95, 1.0, 1.2, 1.5, 1.75, 1.9, 2.0, 2.25, 2.5, 2.75, 3.0, 3.5 or 3.8 mg/kg; and said SNRI compound is desvenlafaxine and is to be administered in a daily dose ranging between 50 and 250 mg of the active ingredient. Accordingly, in an aspect, the invention relates to a composition as described herein, further comprising an SSRI in a unitary dose as indicated above. It is to be understood that these doses are unitary doses, and may be divided over several fractional doses per day.

In another embodiment, said SRI is an SNDRI compound selected from the group consisting of NS 2330; NS 2359, McN 5652; DOV 216,303 and DOV 21 ,947; more preferably NS 2359 or DOV 216,303; or a pro-drug or an active metabolite thereof; or a pharmaceutically acceptable salt thereof.

The invention, now being generally described, will be more readily understood by reference to the following tables and examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention and are not intended to limit the invention.

EXAMPLES EXAMPLE 1 : Foregoing pipamperone-trazodone treatment in major depressive disorder: a placebo and active controlled period finding clinical trial

Table 2 represents the set-up of a clinical trial comprising for treatment groups:

Group Pic - Active / Day 0 represents the group receiving 75 mg trazodone, twice a day, starting the first day (Day 0) of active treatment in the clinical trial. This administration regime is also indicated as the mono therapy.

Group Pip - Active / Day 0 represents the group receiving a combination of 5 mg pipamperone and 75 mg trazodone, twice a day, starting the first day (Day 0) of active treatment in the clinical trial. This administration regime is also indicated as the non- foregoing combo therapy.

Group Pip - Active / Day 4 represents the group receiving 5 mg pipamperone, twice a day, starting the first day (Day 0) of active treatment in the clinical trial, followed by a combination of 5 mg pipamperone and 75 mg trazodone, twice a day, starting the fifth (Day 4) day of active treatment in the clinical trial. This administration regime is also indicated as the foregoing therapy with combination therapy starting after 4 days of active treatment.

Group Pip - Active / Day 7 represents the group receiving 5 mg pipamperon, twice a day, starting the first day (Day 0) of active treatment in the clinical trial, followed by a combination of 5 mg pipamperone and 75 mg trazodone, twice a day, starting the eight (Day 7) day of active treatment in the clinical trial. This administration regime is also indicated as the foregoing therapy with combination therapy starting after 7 days of active treatment.

All subjects also undergo a placebo (PLC) run-in therapy, administered during a period of about 7 days before the active treatment starts.

During daily (D), weekly (W) or monthly (M) visits, several parameters are measured.

Under NECT is to be understood: Neuronal E-clinical Trial = Vesalius Expert development for this trial which includes the bottom-up measurement of:

- In- and exclusion-criteria

- Functional status evaluation

- Medical history

- (Pre-)treatment signs & symptoms

- DSM-IV rules for diagnosis & efficacy

- HDRS-28 (Hamilton Depression Rating Scale - 28 items)

- Medical resource utilisation

- Pre-trial & Concomitant medication

- Drug administration

- (Serious) Adverse events

- Admission to the acute and extension phase of treatment

- Right flow of the trial

EXAMPLE 2: combo pipamperone-trazodone: therapeutic use in Major Depression

Purpose

Pipamperone, administered to patients in a dose ranging between 5 and 15 mg is claimed via its specific pharmacological properties to be a booster of the antidepressant effect of the SARI trazodone. The mechanism of boosting of pipamperone has to deal with (i) the selective affinity for the dopamine-4 (D4) receptor with a pKi value equal to or higher than 8 towards the D4 receptor and less than 8 towards other dopamine receptors, and (ii) the selective affinity for the 5-HT₂A receptor with a pKi value equal to or higher than 8 towards the 5-HT₂A receptor and less than 8 towards other 5-HT receptors. This semi-naturalistic open label study investigated the efficacy and tolerability of the combo pipamperone - trazodone in the treatment of patients with major depression. Details

Semi-naturalistic i.e. inclusion of every 'natural' patient in an outpatient practice but without concomitant use of mood enhancing drugs, open label

No

Phase I la - preliminary Proof of Concept

Belgium - Research Centre ANIMA, Aiken

Assessment scale scores, Hamilton Depression Rating Scale 17 items, Reduction, Response, Remission

Exclusion of mood stabilisers, antipsychotics (typical and atypical) and other antidepressants

Subjects

Patients have a major depressive disorder according to DSM-IV criteria, with or without a chronic course and a treatment refractory state towards another SARI or SRI than trazodone.

Treatments

PIP-TRAZ¹ add-on: trazodone from day minus 60-20 - pipamperone from DAY 0

Drug/Treatment Dose (total) Route Duration

Pipamperone¹ + Pip.: 5-15 mg/day

PO 8 weeks

Trazodone¹ Traz.: 100-300 mg/day

1. Pipamperone (Pip) and trazodone (Traz) dosage was adjusted according to clinical response.

PIP-TRAZ¹ fore-going 1-5: pipamperone from day 0 - trazodone from day 1-5 Drug/Treatment Dose (total) Route Duration

Pipamperon¹ + Pip.: 16-19 mg/day -

PO 8 weeks

Trazodone¹ Traz.: 100-300 mg/day

1. Pipamperone (Pip) and trazodone (Traz) dosage was adjusted according to clinical response. PIP-TRAZ¹ fore-going 6-8: pipamperone from day 0 - trazodone from day 6-8

Drug/Treatment Dose (total) Route Duration

Pipamperon¹ + Pip: 16-19 mg/day

PO 8 weeks

Trazodone¹ Traz: 100-300 mg/day

Results

The results for the add-on, foregoing 1-5 and foregoing 6-8 PIP-TRAZ are compared with:

(1) standard efficacy of antidepressants in clinical trials according to Khan et al. (2000), in "Symptom Reduction and Suicide Risk in Patients Treated With Placebo in Antidepressant Clinical Trials" (Arch, of General Psychiatry, Vol. 57, April 2000). (2) HDRS-17 change from baseline vs SNRI (duloxetine) in Major Depression; the SNRI (duloxetine) treatment was 40-120 mg/day (n = 152) according to Goldstein et al., (Clin. Psychiatry).

(3) remission rates (HDRS-17 <=7) vs SSRIs vs placebo in Major Depression; treatment with SSRIs is according to a meta-analysis of Thase et al. (Br. J. Psychiatry (2001) 178:234-241). Treatment with placebo is according to a meta-analysis of Thase et al.

(Br. J. Psychiatry (2001) 178:234-241).

(4) WO2005/053796 Adverse Events

Adverse events are assessed on: body as a whole, central and peripheral nervous system, gastrointestinal, musculoskeletal, psychiatric, respiratory, skin and appendages, vascular and urinary, taking into account discontinued treatment due to adverse events. Laboratory parameters, ECG, bodyweight and vital signs are not measured since this is a naturalistic study.

Study Messages

The boosting effect of pipamperone at an unconventional low dose on a SARI, in this case trazodone, is apparent.

The combination pipamperone-trazodone is generally well tolerated in patients with depression i.e. at least no specific added adverse events are expected by adding pipamperone at the doses used in the study.

Sedative effects of pipamperone, which are observed at higher doses, are lacking.

EXAMPLE 3: POC process for major depressive disorder

Concept:

Combo of the high selective 5-HT2A/D4 antagonist pipamperone with:

trazodone;

a fore-going admission during 4 days of pipamperone;

a dose of pipamperone of 10 mg/day

Objectives:

Demonstrating that this combo therapy has:

the potency of being a treatment standard for depression by having an added value of reducing the total score of the Hamilton Depression Rating Scale-17 items (HDRS-17) after 8 weeks of therapy with a least 20% more than reached with the conventional known antidepressants, i.e. 60% versus 40%. This stands for an added medium demission of 5 points on the total score of the HDRS-17 and by this will be very highly significant since the mean difference in all recent clinical trials between placebo and active treatment is 2.5; a more sustained therapeutic effect than the conventional mono therapy by preventing significant more relapses during 48 weeks following the acute treatment; and/or

a complete neutral safety profile, e.g. there are no more adverse events in the combo therapy then in mono admission of the in the combo used antidepressant compound.

Process:

The following different steps are implemented to reach out for these objectives (see also Table 2):

(1) an naturalistic open label study (n=>20) on a depressive population with a normal variability of medical and psychiatric history, course of depression, earlier and concomitant therapy admitting the antidepressant trazodone 100-300 mg/day and a dose of 5-15 mg/day of pipamperone in a foregoing, simultaneous or add-on use. (2) a 16 weeks placebo controlled randomised four armed study of each 36 patients with a mayor depressive disorder admitting:

from day 0: pipamperone (PIP) 10 mg/day or an active antidepressant compound or the combination of the last two;

from day 4: pipamperone 10 mg/day combined with and without an active antidepressant compound or an active antidepressant compound without pipamperone;

from day 7: pipamperone 10 mg/day combined with an active antidepressant compound or an active antidepressant compound without pipamperone.

By including rigorous control groups (placebo and active comparator; see Table 2) this clinical trial is evaluated as a proof of concept of the added value of the combo and the foregoing treatment method since the inclusion/exclusion of:

a negative trial, i.e. no significant difference between the placebo and active treatment with the comparator;

a failed trial, i.e. no significant difference between the active and the studied treatment i.e. the combo.

(3) an active controlled randomised relapse prevention study following the POC trial during another 36 weeks with three arms of each 36 patients which is formed by: continuation of the active mono therapy;

randomising the patients with a combo therapy in a group with an active mono therapy and with a continuation of the combo treatment. EXAMPLE 4: combo pipamperone-trazodone: therapeutic use in Obsessive- Compulsive Disorder (OCD).

Purpose

Pipamperone (1 '-[3-(p-Fluorobenzoyl)propyl]-[1 ,4'-bipiperidine]-4'-carboxamide), the active ingredient of Dipiperon (Janssen-Cilag B.V), is administered to a patient in a dose ranging between 5 and 15 mg, is claimed via its specific pharmacological properties to be a booster of the effect of the SARI trazodone towards OCD. The mechanism of boosting of pipamperone has to deal with (i) the selective affinity for the dopamine-4 (D4) receptor with a pKi value equal to or higher than 8 towards the D4 receptor and less than 8 towards other Dopamine receptors, and (ii) the selective affinity for the 5-HT₂A receptor with a pKi value equal to or higher than 8 towards the 5- HT₂A receptor and less than 8 towards other 5-HT receptors. This semi-naturalistic open label study investigates the efficacy and tolerability of the combo pipamperone - trazodone in the treatment of patients with OCD.

Details

Design: Semi-naturalistic i.e. inclusion of every 'natural' patient in an outpatient practice but without concomitant use of anxiolytics, open label

Control: No

Phase: Phase I la - preliminary Proof of Concept

Location: Belgium - Research Centre ANIMA, Aiken

End Points Assessment scale scores, Yale-Brown Obsessive-Compulsive Scale,

Reduction, Remission

Medication: Exclusion of mood stabilisers, antipsychotics (typical and atypical) and other antidepressants and anxiolytics

Subjects

Characteristics: patients have an obsessive-compulsive disorder according to DSM-IV criteria, with or without a chronic course and a treatment refractory state towards another SARI or SRI than trazodone. Treatments

PIP-TRAZ ADD-ON: trazodone from DAY minus 730-60 - pipamperone from DAY 0, in which Pipamperone (Pip) and Trazodone (Traz) dosage is adjusted according to clinical response.

PIP-TRAZ FORE-GOING 4-6: pipamperone from DAY 0 - trazodone from DAY 4-6, in which Pipamperone (Pip) and Trazodone (Traz) dosage is adjusted according to clinical response.

Results

The results are scored via Y-BOCS total score: "fore-going" and "add-on" treatment with pipamperone (5-15 mg/day) and trazodone (100-300 mg/day; bid) in comparison with the SSRI fluvoxamine in OCD. Treatment with the combo pipamperone-trazodone (n = 7). Treatment with fluvoxamine (controlled release) mean 271 mg/day (n = 253) is according to Hollander et al. (2003).

The intention-to-treat/last-observation-carried-forward analysis is evaluated relating to therapeutic efficacy according Y-BOCS total score, obsession and compulsion scores.

Assessment

Efficacy: the combo pipamperone 5-15 mg/day - trazodone 100-300 mg/day is assessed with the in the art known compounds effective towards OCD (Hollander E, Koran LM, Goodman WK, Greist JH, Ninan PT, et al. A double-blind, placebo- controlled study of the efficacy and safety of controlled-release fluvoxamine in patients with obsessive-compulsive disorder. Journal of Clinical Psychiatry 64: 640-647, June 2003 Mount Sinai School of Medicine, New York, New York, USA; Solvay Pharmaceuticals Inc., Marietta, Georgia, USA).

Study Messages

The boosting effect of pipamperone at an unconventional low dose on a SARI is studied relating to the efficacy of the 'add-on' and 'fore-going' combo 'pipamperone 5- 15 mg/day - trazodone 100-300 mg/day' in the treatment of patients with obsessive- compulsive disorder. The combination pipamperone-trazodone is assessed in patients with OCD, no specific added adverse events are expected by adding pipamperone at the doses used in the study.

EXAMPLE 5: combo pipamperone-trazodone: therapeutic use in Panic Disorder.

Purpose Preliminary examination of a "fore-going" and "add-on" treatment with pipamperone (5-15 mg/day) and trazodone (100-300 mg/day) in comparison with the SARI in Panic Disorder.

Subjects

Characteristics: patients have Panic Disorder according to DSM-IV criteria.

Treatments

PIP-TRAZ ADD-ON: trazodone from DAY minus 24-2 months - pipamperone from DAY 0, in which Pipamperone (Pip) and Trazodone (Traz) dosage is adjusted according to clinical response.

Details

Control: No

Phase: Phase I la - preliminary Proof of Concept

Location: Belgium - Research Centre ANIMA, Aiken

End Points Assessment scale scores, CGI-severity score, Reduction, Remission Medication: Exclusion of mood stabilisers, antipsychotics (typical and atypical) and other antidepressants and anxiolytics Results

The results are depicted by the CGI-severity score: "fore-going" and "add-on" treatment with pipamperone (5-15 mg/day) and trazodone (100-300 mg/day) in comparison with the SARI in Panic Disorder. Treatment with paroxetine is according to the Journal of Clinical Psychiatry (2004) 65: 405-413. Treatment with Sertraline is according to the Journal of Clinical Psychiatry (2004) 65: 405-413.

Treatment regimen: A: PLC + PLC

B: 2x(PLC+PIP(5mg))/d

C: 2x(TRAZ(75mg)+PIP(5mg))/d

D: 2x(TRAZ(75mg)+PLC)/d

•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

Claims

1. A pharmaceutical composition comprising pipamperone in a dose between 0.1 and 20 mg or a pharmaceutically acceptable salt thereof and at least one serotonin antagonist and reuptake inhibitor (SARI), or a pharmaceutically acceptable salt thereof, or a derivative thereof or an active metabolite thereof.

2. The composition according to claim 1 , comprising pipamperone in a dose between 5 and 15 mg.

3. The composition according to claim 1 or 2, wherein said SARI is selected from the group consisting of trazodone, etoperidone, nefazodone, and lubazodone.

4. The composition according to any one of claims 1 to 3, wherein said SARI is trazodone, or a pharmaceutically acceptable salt thereof, or a derivative thereof or an active metabolite thereof.

5. The composition according to any one of claims 1 to 4, wherein the dose of said SARI is between 20 and 600 mg.

6. The composition according to any one of claims 1 to 5, wherein the dose of said SARI is between 40 and 400 mg.

7. The composition according to any one of claims 1 to 6, wherein said pipamperone and said SARI are the sole pharmaceutically active ingredients.

8. The composition according to any one of claims 1 to 7, further comprising at least one pharmaceutically acceptable excipient.

9. The composition according to any one of claims 1 to 8, wherein at least said SARI is formulated for extended release.

10. The composition according to any one of claims 1 to 9, for use in treating a disorder characterized by an underlying emotion dysregulation.

1 1. The composition according to claim 10, wherein said disorder is selected from the group consisting of mood disorder and anxiety disorder.

12. The composition according to claim 11 , wherein said mood disorder is Major Depressive Disorder.

13. The composition according to any one of claims 10 to 12, wherein said dose is to be administered daily.

14. The composition according to claim 13, wherein said dose is to be divided for multiple administrations per day.

15. The composition according to any one of claims 10 to 14, wherein said pipamperone and said SARI are to be administered simultaneously or sequentially.

16. The composition according to claim 15, wherein said SARI is to be administered at least one day after the onset of administration of said pipamperone.