WO2020094591A1

WO2020094591A1 - Pde10a inhibitors for treating negative symptoms and cognitive impairments in a patient suffering from schizophrenia

Info

Publication number: WO2020094591A1
Application number: PCT/EP2019/080151
Authority: WO
Inventors: Jacob Nielsen; Raimund Buller
Original assignee: H. Lundbeck A/S
Priority date: 2018-11-06
Filing date: 2019-11-05
Publication date: 2020-05-14
Also published as: TW202031250A; BR112020013820A2

Abstract

The present invention relates to PDE10A inhibitors and compositions comprising PDE10A inhibitors for treating negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in schizophrenia.

Description

PDE10A INHIBITORS FOR TREATING NEGATIVE SYMPTOMS AND COGNITIVE IMPAIRMENTS IN A

PATIENT SUFFERING FROM SCHIZOPHRENIA

FIELD OF THE INVENTION

The present invention relates to PDE10A inhibitors and compositions comprising PDE10A inhibitors for treating negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions, particularly in schizophrenia.

BACKGROUND OF THE INVENTION

Schizophrenia is a psychiatric disorder characterized by three main symptom domains; positive symptoms (delusions, hallucinations, or disorganized/catatonic behavior etc.), negative symptoms (affective flattening, social withdrawal, asociality, anhedonia, avolition, blunted affect, alogia, psychomotor poverty, or poverty of thought and content of speech etc.), and symptoms of cognitive dysfunctions (impaired executive functioning, working memory, attention deficits, social cognitive impairment, jumping to conclusions, Theory of Mind (TOM) impairments, deficits in emotion recognition or affect discrimination etc.). Further information regarding schizophrenia and related diagnosis as well as the various symptom domains described above are available in e.g. the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), American Psychiatric Publishing, 2013.

Negative symptoms and cognitive impairments are also a predominant part of the prodromal phase of schizophrenia, sometimes referred to as psychosis prodrome. The prodromal phase of schizophrenia is characterized by a heterogeneous group of behaviors temporally related to the onset of psychosis. Accordingly, the prodromal phase of schizophrenia can be defined as the time interval from the onset of unusual behavioral symptoms to the onset of psychotic symptoms. An individual who is in the prodromal phase of schizophrenia is at clinical high risk of developing psychosis, which can be assessed by suitable diagnostic tools, such as the Structured Interview for Prodromal Syndromes (SIPS) (Miller TJ, et. al, 2003, Schizophr Bull., 29(4): 703-15). A US study from 2012 revealed that 82% of individuals at clinical high risk of developing a psychosis had at least one negative symptom, which was above moderate in severity. The most frequently reported negative symptoms were "deterioration in role functioning", "avolition" and "social withdrawal" and the negative symptoms were more severe and persistent in clinical high-risk individuals who developed a psychosis within the 12 months following the assessment (Piskulic D, et al., 2012, Psychiatry Res., 196(0): 220-224).

While negative symptoms are a well-documented aspect of schizophrenia (Owen M.J et al., Lancet, 2016, 388(10039): 86-97), this symptom domain has also been identified in non-schizophrenic patients suffering from other psychiatric and neurological disorders e.g. Alzheimer's disease and other dementias, such as frontotemporal dementia (FTD), Huntington's disease, autism spectrum disorder (ASD), bipolar disorder (BPD), stress disorders, anxiety disorders, major depressive disorder (MDD), Parkinson's disease, temporal lobe epilepsy, stroke, and traumatic brain injury (TBI) (Boone et al., 2003, J Int Neuropsychol Soc., 9, 698- 709; Bastiaansen, J. et al., 2011, J. Autism Dev. Disord., 41: 1256-1266; Bogdan and Pizzagalli, 2006, Biol Psychiatry, 60: 1147-1154; Cicero, D.C et al., 2016, Assessment, 23(5) : 544-556; Getz, K. et al., 2002, Am J. Psychiatry, 159: 644-651; Winograd-Gurvich, C. et al., 2006, Brain Res. Bulletin, 70: 312-321; Galynker et al., 2000, Neuropsychiatry Neuropsychol Behav Neurol, 13: 171-176; Galynker I, et al., 1997, J. Nerv. Ment. Dis, 185: 616-621; Chaudhury S., et al., 2005, Indian J. of Neurotrauma, 2: 13-21; Ameen, S., et al., 2007, German J. of Psychiatry, 10(1): 1-7).

In some patient groups, these negative symptoms are generally referred to as apathy. This is true for both Parkinson's and Alzheimer's patients, as well as patients with associated dementias, frontotemporal dementias and stroke (Robert P. et al., 2009, European Psychiatry, 24, 98-104). In these patients, the apathy is characterized by the loss of initiation and motivation to participate in activities, social withdrawal, and emotional indifference. Patients with apathy are at increased risk to progressively suffer from decreased daily function and specific cognitive deficits such as executive cognitive dysfunction. In Alzheimer's disease and Parkinson's disease the apathy symptoms exist alongside the neurodegenerative symptoms classically associated with such diseases. The level of apathy related symptoms in a patient can be assessed by e.g. the Neuropsychiatric Inventory (NPI) instrument, the Structured Clinical Interview for Apathy (SCIA), the Apathy Evaluation Scale (AES), the Apathy Scale (AS), the Apathy Inventory (Al) and/or the Lille Apathy Rating Scale (LARS) (Cummings JL et al., 1994, Neurology, 44, 2308-14; Robert P. et al., 2009, European Psychiatry, 24, 98-104). Currently, most available antipsychotics improve positive symptoms of schizophrenia, while failing to manage the negative symptoms and cognitive dysfunctions adequately. This leaves a significant unmet need for satisfying treatment options for the subpopulation of up to 35-40% of schizophrenic patients, who suffers from persistent negative symptoms (Mucci A. et a I., 2017, Schizophrenia Research, Vol 186, 19-28; Rabinowitz J. et al., 2013, Schizophr Res., 150(2-3), 339-342). Poorly managed negative symptoms are also present in 50 to 60 % of schizophrenic patients, who are considered clinically stable with regards to their positive symptoms and this constitute a major source of impaired functioning in this patient group (Bobes J. et al., 2010, J Clin Psychiatry, 71(3), 280-286).

Moreover, most available antipsychotics is known to cause severe side-effects such as extrapyramidal symptoms (EPS). Therefore, the search for CNS active drugs with improved efficacy on negative and cognitive symptoms as well as better side effect profiles, is important to the development of better treatment options for patients suffering from persistent negative symptoms, persistent prominent negative symptoms, and/or cognitive dysfunctions, particularly in schizophrenia. Such new treatments may also prove beneficial for non-schizophrenic patients suffering from negative symptoms and cognitive impairments.

In this regard, phosphodiesterase 10A (PDE10A) inhibitors were predicted to represent a different mechanism of action useful for the treatment of all symptom domains in schizophrenia; positive symptoms, negative symptoms, and cognitive dysfunction. The PDE10A enzyme is expressed both in D1 and D2 type medium spiny neurons (MSNs) of the striatum and the function of this enzyme is to hydrolyze the 3'-ester bond found in the signalling molecules cAMP and cGMP. This hydrolyzation transforms cAMP and cGMP into their inactive forms; 5'AMP and 5'GMP, respectively (Fujishige K. et al., 1999, J Biol Chem., 274(26): 18438-18445). Accordingly, inhibition of PDE10A will result in elevated levels of both cAMP and cGMP in D1 and D2 type MSNs and consequently, PDE10A inhibitors are expected to positively modulate (activate) signalling from dopamine D1 receptors via the direct pathway and negatively modulate (inhibit) signalling from dopamine D2 receptors via the indirect pathway (Polito M. et al., 2015, eNeuro, 31, 2(4)).

Current antipsychotic drugs act primarily on D2 and hence, act mainly via the indirect pathway. This mechanism of action is known to have beneficial effects against positive symptoms of schizophrenia (Ginovart N. and Kapur S., 2012, Handb Exp Pharmacol, 212, 27-52). In view of this knowledge it follows that increased cAMP levels mediated by PDE10A inhibition in the indirect pathway may have similar beneficial effects against positive symptoms in schizophrenia as the known antipsychotic drugs. Furthermore, negative and cognitive symptoms of schizophrenia are believed to be associated with reduced dopamine function of the direct pathway (Dl) (Heckman R. A. et al, 2016, International Journal of Neuropsychopharmacology, 19(10), 1-16). In view of this knowledge it follows that increased cAMP levels mediated by PDE10A inhibition in the direct pathway could potentially also have beneficial effects on negative symptoms as well as cognitive dysfunctions. This anticipation has been supported by in vivo studies showing that PDE10A2 deficient mice exhibit increased social interaction behavior (Sano H, et al. 2008, J Neurochem, 105(2), 546-56).

Based on the scientific rational outlined above it has been speculated in the scientific community that PDE10A inhibitors could embody a new class of antipsychotics, which could provide efficacy on all three symptom domains of schizophrenia (positive, negative and cognitive symptoms), concurrently (Kehler and Nielsen, 2011, Current Pharmaceutical Design, 17: 137-150; Kehler et al., 2007, Expert Opinion on Therapeutic Patents, 17:2,147-158; Dunlop et al., 2015, Journal of Psychopharmacology, 29(2), 230-238; Arnt J. et al., 2008, Drugs of the Future, 33(9): 777-791; Siuciak J., 2008, CNS Drugs; 22(12): 983-993). This anticipation was further supported by a vast number of scientific studies and patent applications describing the potential clinical utility of various PDE10A inhibitors within schizophrenia, such as MP-10, which is also known as PF-02545920, TP-10, Papaverine, RG7203, THPP-1 and TAK-063 (Langen et al., 2012, Psychopharmacology, 2: 221-249; Grauer et al., 2009, JPET, 331 (2), 574-590; Hano et al., 2008, J Neurochem., 105(2): 546-56; Smith SM. et al., 2013, Neuropharmacology, 64: 215-23; Suzuki and Kimura, 2018, CNS Neurosci Ther., 24(7): 604-614; W02013/178572; W02014/072261; W02015/078836; WO2011/089132; W02011/117264; W02010/063610; US9,550,784; US8,772,510).

Hoffman - La Roche recently disclosed their findings that the PDE10A inhibitor, RG7203, enhanced performance in tasks probing reward functioning in healthy volunteers suggestive of its potential utility to treat negative symptoms in schizophrenia. This clinical hypothesis was tested in patients with chronic schizophrenia and moderate levels of negative symptoms, who were administered RG7203 as adjunctive treatment to their stable background antipsychotic treatment regimens. This study found that RG7203 displayed the opposite of expected results and actually worsened reward functioning. The results, hence, did not support the utility of PDE10A inhibitors as adjunctive treatment for negative symptoms in patients with schizophrenia (Umbricht D. et a I., 2018, Abstracts for the Sixth Biennial SIRS Conference, S43; Umbricht D. et a I., 2017, Neuropsychopharmacology, 42, T187).

PDE10A inhibitors have recently been moved into clinical development as monotherapy of schizophrenia. Two major clinical trials have been conducted by Pfizer and Takeda, exploring the efficacy of PDE10A inhibitor monotherapy, in cohorts of patients with acutely exacerbated schizophrenia. Pfizer tested their PDE10A inhibitor, MP-10, in clinical trial NCT01175135, and Takeda, tested their PDE10A inhibitor, TAK- 063, in clinical trial NCT02477020. Both trials failed to meet their endpoints (Macek et al, 2019, Schizophrenia Research 204, 289-294; DeMartinis N. et al., 2019, Journal of Clinical Psychopharmacology, 39(4), 318-328) and hence, did not support the utility of PDE10A inhibitors as monotherapy for patients with acutely exacerbated schizophrenia. Following their first failed phase II study, Pfizer moved on to investigate MP-10 in another phase II study, NCT01939548, to explore the efficacy as adjunctive treatment in clinically stable patients with schizophrenia who had a suboptimal response to their current treatment. This study was terminated prematurely due to lack of efficacy as identified in an interim analysis.

Consequently, contrary to the general scientific anticipation of the potential for PDE10A inhibitors to provide new treatment options for schizophrenia, none of the clinical trials have demonstrated positive outcomes on either of the symptom domains i.e. positive, negative and cognitive symptoms. This is true for both monotherapy as well as adjunctive therapy trials. Furthermore, the studies indicate that neither patients with acutely exacerbated schizophrenia, patients with chronic schizophrenia and moderate levels of negative symptoms nor clinically stable patients with suboptimal response to their current treatment antipsychotic treatment had any benefit of treatment with PDE10A inhibitors.

In the wake of their 2 failed clinical phase II trials, Pfizer recently published that the clinical development of MP-10 was terminated because the clinical studies failed to meet their endpoints in treatment of schizophrenia (both as monotherapy and adjunctive therapy). The company also stated that during development preclinical studies had been motivating in regard to the clinical utility of MP-10 in treatment of schizophrenia and demonstrated that MP-10 was efficacious across a broad range of in vivo models of schizophrenia, such as apomorphine-induced climbing, conditioned avoidance response (CAR) in both rats and mice, prepulse inhibition paradigms, and models of cognition such as novel object recognition. Subsequently, the drug was shown to be both safe and well tolerated. Furthermore, the observed MP-10 exposures were within the range predicted to be adequate for demonstrating efficacy. Flowever, taken together the failure of the clinical studies refute the hypothesis that PDE10A inhibitors have use as antipsychotic agents for the treatment of schizophrenia (DeMartinis N. et al., 2019, Journal of Clinical Psychopharmacology, 39(4), 318-328).

Unfortunately, despite the efforts to bring novel treatments, such as PDE10A inhibitors into the clinic to accommodate the significant unmet need for patients suffering from persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms and/or cognitive dysfunctions in particular those related to schizophrenia, the situation for these patients remains unchanged. SUMMARY OF THE INVENTION

The inventors of the present invention have found that PDE10A inhibitors can be useful in treating specific subpopulations of schizophrenic patients, who are phenotypical distinct from acutely exacerbated schizophrenic patients and comprise relevant clinical populations, because a significantly unmet treatment need exist in these subpopulations.

In one embodiment the present invention relates to PDE10A inhibitors, for use in treating negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive impairments in a patient suffering from CNS disorders, in particular a schizophrenic patient with clinically stable positive symptoms, wherein said PDE10A inhibitor is administered as monotherapy.

In another embodiment the present invention also relates to methods of treating persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a patient suffering from CNS disorders, in particular a schizophrenic patient with clinically stable positive symptoms, provided that said PDE10A inhibitor is administered as monotherapy, said method of treatment comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to a patient in need thereof as monotherapy.

In yet another embodiment the present invention relates to use of a PDE10A inhibitor in the manufacture of a medicament for the treatment of persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a patient suffering from CNS disorders, in particular a schizophrenic patient with clinically stable positive symptoms, wherein said PDE10A inhibitor is administered as monotherapy.

In another embodiment the patient to be treated may be a schizophrenic patient or a patient who displays psychosis risk syndrome and/or prodrome of schizophrenia. In a further embodiment the patient to be treated may be suffering from Alzheimer's disease or Parkinson's disease with comorbid apathy.

In a particular aspect of the invention, the PDE10A inhibitor is selected from the group consisting of compound (I), compound (II), MP-10, or a pharmaceutically acceptable salt of any of said compounds. In a particular aspect, the PDE10A inhibitor is compound (I) or a pharmaceutically acceptable salt thereof. DEFINITIONS

The term "and/or" as used in statements like "persistent negative symptoms and/or persistent prominent negative symptoms and/or cognitive dysfunctions" are meant to indicate a pathological state, wherein the patient has either persistent negative symptoms, persistent prominent negative symptoms or cognitive dysfunctions, or a combination of two or all three of these types of symptoms, which are further defined hereinbelow.

The term "negative symptoms" as used herein is meant to describe one or more symptom(s) associated with a CNS disorders, in particular schizophrenia. Specific examples of such symptoms are: alogia, amotivation, anhedonia, asociality, emotional withdrawal, social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking, affective flattening, avolition, poverty of speech, dysphoric mood, lack of insight and demoralisation.

The term "persistent negative symptoms" is meant to describe a clinical state of a patient where the negative symptoms have been persistent for at least about 6 months.

The term "prominent negative symptoms" is meant to describe a clinical state of a patient where the negative symptoms are a prominent part of the patient's clinical presentation.

The term "persistent prominent negative symptoms" are meant to describe "prominent negative symptoms", as defined above, that have been persistent for at least about 6 months.

The term "predominant negative symptoms" are meant to describe a subpopulation of patients with "prominent negative symptoms" who display negative symptoms that are at least moderate in severity, as evaluated on an accepted and validated rating scale (e.g. the PANSS negative symptom score, PANSS Marder Negative Symptom Factor score or the Brief Negative Symptom Scale (BNSS)) and display no or only little positive symptoms (e.g. assessed by the PANSS positive symptom score).

The term "persistent predominant negative symptoms" are meant to describe "predominant negative symptoms", as defined above, that have been persistent for at least about 6 months. The terms "cognitive dysfunction" and "cognitive impairment" are used interchangeably and is meant to describe symptoms affecting cognition such as impaired executive functioning, impaired working memory, attention deficits, social cognitive impairment, jumping to conclusions, Theory of Mind (TOM) impairments, deficits in emotion recognition or affect discrimination.

The term "clinically stable positive symptoms" or "clinically stable phase" as used herein is meant to describe a clinical state of a patient suffering from schizophrenia, who has had no exacerbation of their positive symptoms, for a period of about 6 months. Any positive symptoms, which may be present during the clinically stable phase, should not exceed moderate severity, as evaluated on an accepted and valid rating scale, such as the PANSS.

The term "monotherapy" in the present context is meant to describe the treatment regimen related directly to the schizophrenic diagnosis. Hence, when the present invention describes the use of PDE10A inhibitors as monotherapy, it means that they should not be administered as adjunctive/add-on treatment to any background antipsychotic treatment regimens, which may be comprised of either typical or atypical antipsychotics (examples of such drugs are given below). Consequently, a patient being administered a PDE10A inhibitor as monotherapy for treatment of persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptom, persistent predominant negative symptoms and/or cognitive impairments may in parallel with such treatment receive other drugs to treat potential additional pathological conditions, which are unrelated to the schizophrenic diagnosis.

In the present invention, "antipsychotic drugs" are meant to describe a specific class of drugs, which is primarily used to manage psychosis. In the present invention, "antipsychotic drugs" may for example be selected from the group comprising haloperidol, pimozide, chlorpromazine, fluphenazine, perazine, perphenazine, trifluoperazine, clopenthixol, thiothixene, loxapine, sultopride, iloperidone, lurasidone, paliperidone, risperidone, ziprasidone, aripiprazole, brexpiprazole, cariprazine, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin and sertindole.

In the present context, the term "pharmaceutically acceptable salts is meant to describe both pharmaceutically acceptable salt forms and potentially pharmaceutically acceptable co-crystal forms. BRIEF DESCRIPTION OF FIGURES

Fig. 1 Effect of PDE10A inhibitors in the Conditioned Avoidance Response (CAR) assay in Rats.

Fig. 2 Effect of PDE10A inhibition on synaptic transmission in brain slices from rat prefrontal cortex.

Fig. 3 PDE10A inhibition modulates cAMP in both dopamine D1 and D2 receptor expressing neurons of the striatum.

Fig. 4 Effect of PDE10A inhibitors on social interaction deficit.

Fig. 5 The chronic mild stress (CMS) model used to assess stress-induced hedonic deficits.

Fig. 6 The novel object recognition (NOR) task in rats.

DETAILED DESCRIPTION OF THE INVENTION

The inventors of the present invention have surprisingly found that when animals are administered a low dose of amphetamine to mimicking patients with exacerbated positive symptoms and tested in the conditioned avoidance response (CAR) assay, the antipsychotic effect of PDE10A inhibitors, which is seen in control animals, is abolished (figure 1). This finding strongly indicates that schizophrenic patients with exacerbated positive symptoms are not a well-suited patient group to treat with PDE10A inhibitors. This finding is unexpected in view of the general anticipation that PDE10A inhibitors could be useful as antipsychotic treatment as described in prior art.

Thus, without wishing to be bound by a pa rticular theory, the inventors found that the effect of PDE10A inhibition is altered in animal models that mimic conditions with increased striatal dopamine tonus. Consequently, the inventors have identified that PDE10A inhibitors display an altered mechanism of action in physiological states with high dopamine, which is illustrated in example 1 and figure 1.

This new understanding of PDE10A inhibitor's mechanism of action indicates that the patient groups that are suitable to receive treatment with PDE10A inhibitors should unexpectedly be selected from the group comprising the following subpopulations of schizophrenic patients: patients with negative symptoms, patients with persistent negative symptoms, patients with prominent negative symptoms, patients with persistent prominent negative symptoms, patients with predominant negative symptoms, patients with persistent predominant negative symptoms, patients with cognitive dysfunctions, patients with cognitive impairments and patients displaying a combination of characteristics associated with such subpopulations, wherein said patients are further characterized by being in a clinically stable phase in regards to their positive symptoms, such as patients who do not display strong positive symptoms as a part of their clinical presentation or patients who have pharmacologically well-managed positive symptoms. In a further aspect the patient groups described above who have pharmacologically well- managed positive symptoms is switched from their current antipsychotic treatment regimen onto a PDE10A inhibitor monotherapy regimen. In a specific embodiment of the invention the negative and/or cognitive symptoms observed in any of the subpopulations of schizophrenic patients described above is treated by administering a therapeutically effective amount of a PDE10A inhibitor, such as Compound (I), Compound (II) or MP-10 as monotherapy.

These patient subgroup as described herein above are phenotypically distinct from acutely exacerbated schizophrenic patients and schizophrenic patients with strong positive symptoms, and these subpopulations comprise highly relevant clinical populations, because a significant unmet treatment need exist in these subpopulations.

In one embodiment, the phenotypical distinction of the above-mentioned subpopulations from acutely exacerbated schizophrenic patients, originates from a specific clinical presentation of the schizophrenic symptoms, wherein the negative and/or cognitive symptoms constitute the majority of the patient's symptoms associated with schizophrenia, meaning that these patients have a specific disease presentation with none or only little positive symptoms. In another embodiment, the phenotypical distinction of the above-mentioned subpopulations from acutely exacerbated schizophrenic patients, originates from a clinical efficacious management of the positive symptoms with antipsychotics, while the negative and/or cognitive symptoms are not well-treated, meaning that the patient has well-treated and clinically stable positive symptoms, but that the negative and/or cognitive symptoms remains and currently constitute the majority of the displayed symptoms associated with schizophrenia. In an aspect of the invention, the monotherapeutic treatment with a PDE10A inhibitor maintains stability of the positive symptoms and prevents exacerbations, while providing beneficial effect on the poorly-managed negative and/or cognitive symptoms. In yet another aspect, the patient who currently has clinical efficacious management of their positive symptoms with antipsychotics, while the negative and/or cognitive symptoms are not well-treated, is switched from the current antipsychotic treatment onto treatment with a PDE10A inhibitor administered as monotherapy. Such switch in treatment will maintain of the clinical stability of the positive symptoms, while providing reduction in the severity and/or amount of negative and/or cognitive symptoms.

The PDE10A inhibitors have no target overlap with classic antipsychotics, which will likely reduce common peripheral side effects normally observed with such drugs, e.g. weight gain. It is an object of the present invention to provide new methods of treatment of negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions, particularly in schizophrenic patients with no exacerbated positive symptoms.

In an embodiment of the invention, PDE10A inhibitors are believed to be useful in treating negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms and/or persistent predominant negative symptoms in patients which, despite on-going standard of care with e.g. antipsychotic therapy, continue to be socially withdrawn or amotivated/emotionless and limited in their interaction with their surroundings, which may significantly diminishes their quality of life. In another embodiment, the present invention discloses that PDE10A inhibitors exhibit their primary efficacy on negative symptoms and/or cognitive dysfunctions, but that this effect is abolished when the striatal level of dopamine is elevated, such as in states of acutely exacerbated schizophrenia.

In a separate embodiment, the invention provides new methods for the treatment of individuals who are in the prodromal phase of schizophrenia. Such individuals can for example be identified with suitable valid questionnaires, such as the Structured Interview for Prodromal Syndromes (SIPS). In this type of patient, the treatment with a PDE10A inhibitor may represent a prophylactic treatment strategy, which can ameliorate present symptoms as well as potentially delay or prevent future psychotic incidents.

In another embodiment, the invention also relates to PDE10A inhibitors for use in a method for treating a patient suffering from cognitive dysfunction/impairment, provided that the PDE10A inhibitor is administered as monotherapy - these patients may or may not be schizophrenic.

In a particularly embodiment, the invention relates to PDE10A inhibitors for use as monotherapy in a method for treating schizophrenic patients with prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms and/or persistent predominant negative symptoms, wherein the patients are in a clinically stable phase with respect to the patient's positive symptoms.

Since negative symptoms and/or cognitive dysfunctions are known to be present in many patient groups outside of schizophrenia, where dopamine levels are normal, such patients will likely also benefit from treatment with PDE10A inhibitors. Hence, in a separate embodiment PDE10A inhibitors is useful in the treatment of non-schizophrenic patients suffering from negative symptoms and/or cognitive dysfunctions. In an aspect this include patients who suffers from Alzheimer's disease or Parkinson's disease. In a particular aspect these patients have comorbid apathy associated with Alzheimer's disease or Parkinson's disease.

Compounds that are potent PDE10A inhibitors may be identified by testing their inhibitory potency in a PDE10A inhibition assay. Such assay may for example be performed by mixing a fixed amount of the PDE10A enzyme and varying amounts of the compound to be tested. The assay is initiated when a fixed amount of labelled cyclic nucleotide substrate is added to the enzyme-inhibitor mix. Following this step, the a mount of converted substrate can be measured for various concentrations of the inhibitor compound and compared to the amount found in an uninhibited control (100 %). The concentration of the compound to be tested, which result in a 50% reduction of the substrate conversion is known as the IC50, and this value is used to define the potency of a specific compound. An example of such inhibition assay is further described in W02009/152825. The PDE10A Inhibitors of the present invention is considered potent when the IC50 < 1000 nM, more preferably IC50 < 100 nM, IC50 < 50 nM, IC50 < 10 nM and even more preferably IC50 < 5 nM.

In one embodiment, the PDE10A inhibitor of the invention is a small molecule, which is a potent PDE10A inhibitor. Such small molecules may originate from various chemical scaffolds selected from the group comprising: phenylimidazole, imidazole, isoquinoline, quinoline, cinnoline, quinoxaline, quinazoline, naphthyridine, tetrahydropyridopyrimidine, pyrazolopyrimidine and 2-oxindole. Specific compounds which fall within this embodiment are disclosed in W02009/152825, W02012/065612, W02006/072828 and Jankowska et al., 2019, Current Drug Targets, 20, 122-143, which is hereby incorporated by reference in its entirety (to the maximum extent permitted by law).

Specific examples of potent PDE10A inhibitors are illustrated hereinbelow in table 1 and methods for preparation of said PDE10A inhibitors are described in W02009/152825 (see example 12 for preparation of Compound (I)); W02012/065612 (see example 2 for preparation of Compound (II)); and W02006/072828 (see example 3 for preparation of MP-10)). In an embodiment, the PDE10A inhibitor of the present invention is selected from the group consisting of Compound (I) and pharmaceutically acceptable salts thereof, Compound (II) and pharmaceutically acceptable salts thereof and MP-10 and pharmaceutically acceptable salts thereof.

In another aspect of the present invention, the negative symptoms to be treated are primary negative symptoms. Primary negative symptoms are etiological ly related to the core pathophysiology of schizophrenia, whereas secondary negative symptoms are derivatives of other symptoms of schizophrenia (e.g. positive symptoms), other disease processes, medications and/or environment.

In one aspect, the invention is not limited to any specific PDE10A inhibitor(s), since an abundant number of PDE10A inhibitors will be able to provide the technical effect claimed. This statement is further supported in the experimental section (example 1, 4A and 5) where both MP-10, Compound (I) and Compound (II) are shown to be effective in various in vivo assays, even though the chemical structure of these compounds are distinct. The efficacy appears to be occupancy driven and all PDE10A inhibitors are expected to display equivalent pharmacological effect if the suitable occupancy level at the PDE10A receptor is reached. The desired occupancy level can be reached by adjusting the dose and/or the dosing regimen of the PDE10A inhibitor in question to obtain the suitable pharmacokinetic profile. The occupancy can be determined by using a PET ligand capable of binding to the PDE10A receptor in the CNS, an example of such PET ligand is described in W02012/062319.

In one aspect of the present invention, PDE10A inhibitors are used as monotherapy to treat negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a schizophrenic patient who displays no or only little positive symptoms and who are treatment-naive to antipsychotic drugs, i.e. said patient has not previously been treated with any type of antipsychotic. In another aspect, PDE10A inhibitors are used as monotherapy to treat negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a schizophrenic patient who was previously treated with an antipsychotic drug but discontinued such treatment, e.g. because the drug did not provide adequate improvement of the negative symptoms and/or because the subject could not tolerate the side effects of the drug. In yet another aspect of the invention, PDE10A inhibitors are used as monotherapy to treat negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a schizophrenic patient who, up until now, has been treated with an antipsychotic drug but such treatment has not provided adequate improvement in regards to the negative symptoms.

In a particular embodiment, the invention relates to PDE10A inhibitors for use as monotherapy in the treatment of negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a patient suffering from schizophrenia, who are clinically stable in regards to the positive symptoms, or an individual who is in the prodromal phase of schizophrenia. In another embodiment of the invention, the patient to be treated with the PDE10A inhibitor suffers from deficit schizophrenia or residual schizophrenia.

In yet another embodiment of the invention, the patient to be treated with the PDE10A inhibitor suffers from simple type schizophrenia or simple schizophrenia.

In a preferred aspect, the invention relates specifically to the exemplified PDE10A inhibitors; i.e. MP-10, Compound (I) or Compound (II) or a pharmaceutically acceptable salt thereof as monotherapy for the treatment of negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a patient suffering from schizophrenia or are in the prodromal phase of schizophrenia.

In a particular aspect, the invention relates to Compound (I) or a pharmaceutically acceptable salt thereof, for use as monotherapy in the treatment of persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a patient suffering from schizophrenia in a patient suffering from schizophrenia, who are clinically stable in regards to the positive symptoms, or an individual who is in the prodromal phase of schizophrenia. In a specific aspect, the Compound (I) hemiadipate is used as monotherapy to treat persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a patient suffering from schizophrenia, who are clinically stable with reference to the positive symptoms. In another specific embodiment, the Compound (I) hemiadipate is used as monotherapy to treat negative symptoms and/or cognitive impairments in an individual who is in the prodromal phase of schizophrenia.

In an embodiment of the invention, the patient suitable for treatment with a PDE10A inhibitor has schizophrenia diagnosed according to DSM-V and has suffered from persistent prominent or predominant negative symptoms for at least about 6 months. The patient may have been treated with stable doses of an oral antipsychotic and with no dose increase during the last 6 months. In addition, the patient has had no psychiatric admissions/hospitalization due to a clinical deterioration during the last 6 months.

In another embodiment, the patient with clinically stable positive symptoms is characterized by having positive symptoms, which are not more than moderate in severity, that is a score of <4 (moderate) out of a score of 7 on each of the following PANSS items: Delusions (PI), Hallucinatory behavior (P3), Suspiciousness / persecution (P6), Uncooperativeness (G8), Unusual thought content (G9) and a score <5 on Conceptual disorganization (P2). In yet another embodiment the schizophrenic patient suitable for treatment as disclosed in the present invention has prominent or predominant negative symptoms as demonstrated by a PANSS Marder Negative Symptom Factor Score (NSFS) >20. NSFS is the sum of scores of the following PANSS items: Blunted affect (Nl), Emotional withdrawal (N2), Poor rapport (N3), Passive/apathetic social withdrawal (N4), Lack of spontaneity & flow of conversation (N6), Motor retardation (G7) and Active social avoidance (G16).

In an aspect the schizophrenic patient suitable for treatment as disclosed in the present invention has a Clinical Global Impression-Schizophrenia Severity of Illness (CGI-SCH-S) overall severity score <4.

In one embodiment, the treatment effect on the negative symptoms by administration of a PDE10A inhibitor as described in the present invention can be assessed by e.g. a statistically significant change in Negative Symptom Scale (BNSS) total score after 12 weeks of treatment compared to placebo. The BNSS is a brief clinician rating scale, intended to measure negative symptoms. It consists of 13 items organized into 6 subscales: anhedonia, distress, asociality, avolition, blunted affect and alogia. Items 1 to 4 are rated from 0 (Normal) to 6 (Extremely severe) and items 5 to 13 are rated from 0 (No impairment) to 6 (Severe deficit). The BNSS total score is calculated by summing the 13 individual items; subscale scores are calculated by summing the individual items within each subscale. The BNSS total scores ranges from 0 to 78.

Pharmaceutically acceptable salts

The PDE10A inhibitors of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. When said PDE10A inhibitor contains a free base such salts may be prepared by treating a solution or suspension of the free base of the PDE10A inhibitor with a molar equivalent of a pharmaceutically acceptable acid. Representative examples of suitable organic and inorganic acids are described below.

Pharmaceutically acceptable salts in the present context is intended to indicate non-toxic, i.e. physiologically acceptable salts. The term pharmaceutically acceptable salts includes salts formed with inorganic and/or organic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, adipic acid, nitrous acid, sulphuric acid, benzoic acid, citric acid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaric acid, acetic acid, propionic acid, oxalic acid, maleic acid, fumaric acid, glutamic acid, pyroglutamic acid, salicylic acid, salicylic acid and sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid and benzenesulfonic acid. Some of the acids listed above are di- or tri-acids, i.e. acids containing two or three acidic hydrogens, such as phosphoric acid, sulphuric acid, fumaric acid and maleic acid. Di- and tri-acids may form 1:1, 1:2 or 1:3 (tri-acids) salts, i.e. a salt formed between two or three molecules of the compound of the present invention and one molecule of the acid.

Additional examples of useful acids and bases to form pharmaceutically acceptable salts can be found e.g. in Stahl and Wermuth (Eds) "Handbook of Pharmaceutical salts. Properties, selection, and use", Wiley- VCH, 2008.

Therapeutically effective amount:

In the present context, the term "therapeutically effective amount" of a compound means an amount sufficient to alleviate, arrest, partially arrest, remove or delay the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of a PDE10A inhibitor. An amount adequate to accomplish this is defined as "therapeutically effective amount". Effective amounts for each purpose will depend on the severity of the symptoms as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, which is all within the ordinary skills of a trained physician.

Treatment and treating:

In the present context, "treatment" or "treating" is intended to indicate the management and care of a patient for the purpose of alleviating, arresting, partly arresting, removing or delaying progress of the clinical manifestation of the negative symptoms and/or cognitive dysfunctions. In an embodiment, the treatment period is at least one week, at least two weeks, at least four weeks, at least six weeks, at least eight weeks, at least 10 weeks or at least twelve weeks. The patient to be treated is preferably a mammal, in particular a human being.

Administration routes:

The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, buccal, sublingual, transdermal and parenteral (e.g. subcutaneous, intramuscular, and intravenous) route; the oral route being preferred.

It will be appreciated that the route will depend on the general condition and age of the subject to be treated, the nature of the symptoms to be treated and the specific PDE10A inhibitor.

Pharmaceutical formulations and excipients: The present invention also provides new use of pharmaceutical composition comprising one or more PDE10A inhibitors. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable excipients in accordance with conventional techniques such as those disclosed in Remington, The Science and Practice of Pharmacy, 22^th edition (2012), Edited by Allen, Loyd V., Jr.

In the present context, "excipient" or "pharmaceutically acceptable excipient" refers to pharmaceutical excipients including, but not limited to, fillers, antiadherents, binders, coatings, colours, disintegrants, flavours, glidants, lubricants, preservatives, sorbents, sweeteners, solvents, vehicles and adjuvants.

Pharmaceutical compositions for oral administration include solid oral dosage forms such as tablets, capsules, powders and granules; and liquid oral dosage forms such as solutions, emulsions, suspensions and syrups as well as powders and granules to be dissolved or suspended in an appropriate liquid.

Solid oral dosage forms may be presented as discrete units (e.g. tablets or hard or soft capsules), each containing a predetermined amount of the active ingredient, and preferably one or more suitable excipients. Where appropriate, the solid dosage forms may be prepared with coatings such as enteric coatings or they may be formulated so as to provide modified release of the active ingredient such as delayed or extended release according to methods well known in the art. Where appropriate, the solid dosage form may be a dosage form disintegrating in the saliva, such as for example an orodispersible tablet.

Examples of excipients suitable for solid oral formulation include, but are not limited to, microcrystalline cellulose, corn starch, lactose, mannitol, povidone, croscarmellose sodium, sucrose, cyclodextrin, talcum, gelatine, pectin, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Similarly, the solid formulation may include excipients for delayed or extended release formulations known in the art, such as glyceryl monostearate or hypromellose.

If solid material is used for oral administration, the formulation may for example be prepared by mixing the active ingredient with solid excipients and subsequently compressing the mixture in a conventional tableting machine; or the formulation may for example be placed in a hard capsule e.g. in powder, pellet or mini tablet form. The amount of solid excipient will vary widely but will typically range from about 25 mg to about 1 g per dosage unit.

Liquid oral dosage forms may be presented as for example elixirs, syrups, oral drops or a liquid filled capsule. Liquid oral dosage forms may also be presented as powders for a solution or suspension in an aqueous or non-aqueous liquid. Examples of excipients suitable for liquid oral formulation include, but are not limited to, ethanol, propylene glycol, glycerol, polyethylenglycols, poloxamers, sorbitol, poly-sorbate, mono and di-glycerides, cyclodextrins, coconut oil, palm oil, and water.

Liquid oral dosage forms may for example be prepared by dissolving or suspending the active ingredient in an aqueous or non-aqueous liquid, or by incorporating the active ingredient into an oil-in-water or water-in-oil liquid emulsion.

Further excipients may be used in solid and liquid oral formulations, such as colourings, flavourings and preservatives etc.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous solutions, dispersions, suspensions or emulsions for injection or infusion, concentrates for injection or infusion as well as sterile powders to be reconstituted in sterile solutions or dispersions for injection or infusion prior to use.

Examples of excipients suitable for parenteral formulation include, but are not limited to water, coconut oil, palm oil and solutions of cyclodextrins. Aqueous formulations should be suitably buffered if necessary and rendered isotonic with sufficient saline or glucose.

Other types of pharmaceutical compositions include suppositories, inhalants, creams, gels, dermal patches, implants and formulations for buccal or sublingual administration.

It is requisite that the excipients used for any pharmaceutical formulation comply with the intended route of administration and are compatible with the active ingredients.

Doses:

In one embodiment, the PDE10A inhibitors of the present invention are administered in an amount from about 0.001 mg/kg body weight to about 100 mg/kg body weight per day. In particular, daily dosages may be in the range of 0.01 mg/kg body weight to about 50 mg/kg body weight per day. The exact dosages will depend upon the frequency and mode of administration, the sex, the age the weight, and the general condition of the subject to be treated, the nature and the severity of the condition to be treated, any concomitant diseases to be treated, the desired effect of the treatment and other factors known to those skilled in the art.

A typical oral dosage for adults will be in the range of 0.1-1000 mg/day of a compound of the present invention, such as 1-500 mg/day, 1-100 mg/day, 1-50 mg/day, 1-10 mg/day, 2 mg/day, 3 mg/day, 4 mg/day, 5, mg/day or 6 mg/day. Conveniently, the PDE10A inhibitors of the invention are administered in a unit dosage form containing said compounds in an amount of about 0.1 to 500 mg, such as, 2 mg, 3 mg, 4 mg, 5, mg, 6 mg, 10 mg, 50 mg 100 mg, 150 mg, 200 mg, 250 mg or 500 mg.

EMBODIMENTS ACCORDING TO THE INVENTION

In the following, embodiments of the invention are disclosed. The first embodiment is denoted El, the second embodiment is denoted E2 and so forth.

El. A PDE10A inhibitor for use in treating a patient suffering from negative symptoms, provided that said PDE10A inhibitor is administered as monotherapy.

E2. A PDE10A inhibitor for use in treating a patient suffering from persistent negative symptoms, provided that said PDE10A inhibitor is administered as monotherapy.

E3. A PDE10A inhibitor for use in treating a patient suffering from prominent negative symptoms, provided that said PDE10A inhibitor is administered as monotherapy.

E4. A PDE10A inhibitor for use in treating a patient suffering from persistent prominent negative symptoms, provided that said PDE10A inhibitor is administered as monotherapy.

E5. A PDE10A inhibitor for use in treating a patient suffering from predominant negative symptoms, provided that said PDE10A inhibitor is administered as monotherapy.

E6. A PDE10A inhibitor for use in treating a patient suffering from persistent predominant negative symptoms, provided that said PDE10A inhibitor is administered as monotherapy.

E7. Any of the preceding embodiments, wherein the negative symptoms are primary negative symptoms.

E8. Any of the preceding embodiments, wherein the negative symptoms are selected from the group consisting of: alogia, amotivation, anhedonia, asociality, emotional withdrawal, social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking, affective flattening, avolition, dysphoric mood, lack of insight, and demoralisation. E9. Any of the preceding embodiments, wherein the negative symptoms are selected from the group consisting of: social withdrawal, anhedonia and avolition.

E10. A PDE10A inhibitor for use in treating a patient suffering from cognitive impairments, provided that said PDE10A inhibitor is administered as monotherapy.

Ell. A PDE10A for use according to embodiment 10, wherein the cognitive impairment is selected from the group consisting of: impaired executive functioning, impaired working memory and attention deficits.

E12. A PDE10A inhibitor for use according to any of the preceding embodiments, wherein the patient suffers from schizophrenia.

E13. A PDE10A inhibitor for use according to embodiment 12, wherein the schizophrenic patient is in a clinical stable phase.

E14. A PDE10A inhibitor for use according to embodiment 13, wherein the schizophrenic patient is in a clinical stable phase with respect to the patient's positive symptoms.

E15. A PDE10A inhibitor for use according to embodiment 14, wherein the clinical stable positive symptoms are defined by the positive symptoms not surpassing moderate severity.

E16. A PDE10A inhibitor for use according to any of the preceding embodiments, wherein the patient suffers from deficit schizophrenia.

E17. A PDE10A inhibitor for use according to any of the preceding embodiments, wherein the

patient suffers from simple schizophrenia or simple type schizophrenia.

E18. A PDE10A inhibitor for use according to any of the preceding embodiments, wherein the patient suffers from schizotypal personality disorder or schizoaffective disorder. E19. A PDE10A inhibitor for use according to any of embodiments 1-10, wherein the patient displays psychosis risk syndrome and/or prodrome of schizophrenia.

E20. A PDE10A inhibitor for use according to any of embodiments 1-10, wherein the patient is not diagnosed with schizophrenia.

E21. A method of treating a patient suffering from negative symptoms, comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to a patient in need thereof as monotherapy.

E22. A method of treating a patient suffering from persistent negative symptoms, comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to a patient in need thereof as monotherapy.

E23. A method of treating a patient suffering from prominent negative symptoms, comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to a patient in need thereof as monotherapy.

E24. A method of treating a patient suffering from persistent prominent negative symptoms, comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to a patient in need thereof as monotherapy.

E25. A method of treating a patient suffering from predominant negative symptoms, comprising the administration of a therapeutically effective amount of a PDE10A to a patient in need thereof as monotherapy.

E26. A method of treating a patient suffering from persistent predominant negative symptoms, comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to a patient in need thereof as monotherapy.

E27. A method of treating a patient according to any of embodiments 21-26, wherein the negative symptoms are primary negative symptoms. E28. A method of treating a patient according to any of embodiments 21-27, wherein the negative symptoms are selected from the group consisting of: alogia, amotivation, anhedonia, asociality, emotional withdrawal, social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking, affective flattening, avolition, dysphoric mood, lack of insight, and demoralisation.

E29. A method of treating a patient according to any of embodiments 21-28, wherein the negative symptoms are selected from the group consisting of: social withdrawal, anhedonia and avolition.

E30. A method of treating a patient suffering from cognitive impairments, comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to a patient in need thereof as monotherapy.

E31. A method of treating a patient according to embodiment 30, wherein the cognitive impairment is selected from the group consisting of: impaired executive functioning, impaired working memory and attention deficits.

E32. A method of treating a patient according to any of embodiments 21-31, wherein the patient suffers from schizophrenia.

E33. A method of treating a patient according to any of embodiments 21-32, wherein the schizophrenic patient is in a clinical stable phase.

E34. A method of treating a patient according to embodiment 33, wherein the schizophrenic patient is in a clinical stable phase with respect to the patient's positive symptoms.

E35. A method of treating a patient according to embodiment 34, wherein the clinical stable positive symptoms are defined by the positive symptoms not surpassing moderate severity.

E36. A method of treating a patient any of embodiments 21-35, wherein the patient suffers from deficit schizophrenia or residual schizophrenia. E37. A method of treating a patient according to any of embodiments 21-35, wherein the patient suffers from simple schizophrenia or simple type schizophrenia.

E38. A method of treating a patient according to any of embodiments 21-35, wherein the patient suffers from schizotypal personality disorder or schizoaffective disorder.

E39. A method of treating a patient according to any of embodiments 21-31, wherein the patient displays psychosis risk syndrome and/or prodrome of schizophrenia.

E40. A method of treating a patient according to any of embodiments 21-31, wherein the patient is not diagnosed with schizophrenia.

E41. Use of a PDE10A inhibitor in the manufacture of a medicament for the treatment of negative symptoms, provided that said compound is administered as monotherapy.

E42. Use of a PDE10A inhibitor in the manufacture of a medicament for the treatment of persistent negative symptoms, provided that said compound is administered as monotherapy.

E43. Use of a PDE10A inhibitor in the manufacture of a medicament for the treatment of prominent negative symptoms, provided that said compound is administered as monotherapy.

E44. Use of a PDE10A inhibitor in the manufacture of a medicament for the treatment of persistent prominent negative symptoms, provided that said compound is administered as monotherapy.

E45. Use of a PDE10A inhibitor in the manufacture of a medicament for the treatment of predominant negative symptoms, provided that said compound is administered as monotherapy.

E46. Use of a PDE10A inhibitor in the manufacture of a medicament for the treatment of persistent predominant negative symptoms, provided that said compound is administered as monotherapy. E47. Use of a PDE10A inhibitor in the manufacture of a medicament according to any of embodiments 41-46, wherein the negative symptoms are primary negative symptoms.

E48. Use of a PDE10A inhibitor in the manufacture of a medicament according to any of embodiments 41-47, wherein the negative symptoms are selected from the group consisting of: alogia, amotivation, anhedonia, asociality, emotional withdrawal, social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking, affective flattening, avolition, dysphoric mood, lack of insight, and demoralisation.

E49. Use of a PDE10A inhibitor in the manufacture of a medicament according to any of embodiments 41-48, wherein the negative symptoms are selected from the group consisting of: social withdrawal, anhedonia and avolition.

E50. Use of a PDE10A inhibitor in the manufacture of a medicament for the treatment of cognitive impairments, provided that said compound is administered as monotherapy.

E51. Use of a PDE10A inhibitor in the manufacture of a medicament according to embodiment 50, wherein the cognitive impairment is selected from the group consisting of: impaired executive functioning, impaired working memory and attention deficits.

E52. Use of a PDE10A inhibitor in the manufacture of a medicament according to any of embodiments 41-51, wherein the patient suffers from schizophrenia.

E53. Use of a PDE10A inhibitor in the manufacture of a medicament according to any of embodiments 41-52, wherein the schizophrenic patient is in a clinical stable phase.

E54. Use of a PDE10A inhibitor in the manufacture of a medicament according to embodiment 53, wherein the schizophrenic patient is in a clinical stable phase with respect to the patient's positive symptoms. E55. Use of a PDE10A inhibitor in the manufacture of a medicament according to embodiment 54, wherein the clinical stable positive symptoms are defined by the positive symptoms not surpassing moderate severity.

E56. Use of a PDE10A inhibitor in the manufacture of a medicament according to any of embodiments 41-55, wherein the patient suffers from deficit schizophrenia.

E57. Use of a PDE10A inhibitor in the manufacture of a medicament according to any of embodiments 41-55, wherein the patient suffers from simple schizophrenia or simple type schizophrenia.

E58. Use of a PDE10A inhibitor in the manufacture of a medicament according to any of embodiments 41-55, wherein the patient suffers from schizotypal personality disorder or schizoaffective disorder.

E59. Use of a PDE10A inhibitor in the manufacture of a medicament according to any of embodiments 41-51, wherein the patient displays psychosis risk syndrome and/or prodrome of schizophrenia.

E60. Use of a PDE10A inhibitor in the manufacture of a medicament according to any of embodiments 41-51, wherein the patient is not diagnosed with schizophrenia.

E61. Any of the preceding embodiments, wherein the PDE10A inhibitor is administered by any parenteral route in a therapeutically effective amount.

E62. Any of embodiments 1-60, wherein the PDE10A inhibitor is administered by any enteral route in a therapeutically effective amount.

E63. Any of embodiments 1-60 and 62, wherein the PDE10A inhibitor is administered by the oral route in a therapeutically effective amount. E64. Any of the preceding embodiments, wherein the PDE10A inhibitor is administered in a dose between 0.1 - 15 mg/day.

E65. Any of the preceding embodiments, wherein the PDE10A inhibitor is administered in a dose between 1-6 mg/day.

E66. Any of the preceding embodiments, wherein the patient's negative symptoms and/or cognitive impairments are at least moderate in severity.

E67. Any of the preceding embodiments, wherein the patient has a PANSS Marder Negative Symptom Factor Score >20.

E68. Any of the preceding embodiments, wherein the PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by the change in the relevant score on any clinically valid scale to assess such symptoms.

E69. Any of the preceding embodiments, wherein the PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by the change in BNSS score.

E70. Any of the preceding embodiments, wherein the PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by the change in PSP score.

E71. Any of the preceding embodiments, wherein the PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by the change in PANSS score.

E72. Any of the preceding embodiments, wherein the PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by the change in Clinical Global Impression - Schizophrenia (CGI-SCH-S) negative symptom score.

E73. Any of the preceding embodiments, wherein the PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by the change in Clinical Global Impression - Schizophrenia (CGI-SCH-DC) negative symptom score. E74. Any of the preceding embodiments, wherein the PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by the change in Calgary Depression Scale for Schizophrenia (CDSS) total score.

E75. Any of the preceding embodiments, wherein the PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions and the treatment effect has commenced within 12 weeks of administration with said PDE10A inhibitor.

E76. A PDE10A inhibitor for use in the treatment of 22qll.2 deletion syndrome.

E77. A PDE10A inhibitor for use in the treatment of a neurological disorder such as Alzheimer's disease and other dementias, such as frontotemporal dementia (FTD), Huntington's disease, Parkinson's disease, temporal lobe epilepsy, stroke, and traumatic brain injury (TBI).

E78. A PDE10A inhibitor for use in the treatment of apathy and/or cognitive impairments associated with Alzheimer's disease or Parkinson's disease.

E79. Any of the preceding embodiments, wherein said PDE10A inhibitor has an IC50 < 1000 nM.

E80. Any of the preceding embodiments, wherein said PDE10A inhibitor has an IC50 < 100 nM.

E81. Any of the preceding embodiments, wherein said PDE10A inhibitor has an IC50 < 50 nM.

E82. Any of the preceding embodiments, wherein said PDE10A inhibitor has an IC50 < 10 nM.

E83. Any of the preceding embodiments, wherein said PDE10A inhibitor has an IC50 < 5 nM. E84. Any of the preceding embodiments, wherein said PDE10A inhibitor is selected from the group consisting of compound (I), compound (II), MP-10, or a pharmaceutically acceptable salt of any of said compounds:

MP-10:

Compound (1): Compound (SI):

E85. Any of the preceding embodiments, wherein said PDE10A inhibitor is compound (I) or a pharmaceutically acceptable salt thereof:

Compound (I):

E86. Any of the preceding embodiments, wherein said PDE10A inhibitor is a pharmaceutically acceptable salt of Compound (I), which is selected from the group comprising: the hemiadipate, hydrogen bromide, hydrogen chloride, dihydrogen phosphate, hydrogen sulphate, citrate, fumarate, hemifumarate, D-glucoronate, glutarate, 2-oxo-glutarate, L(-)-malate, maleate, malonate, mesylate, oxalate, hemi-succinate, L(+)-tartrate, and tosylate salt of Compound (I):

Compound (I):

E87. Any of embodiments 1-84, wherein said PDE10A inhibitor is compound (II) or a pharmaceutically acceptable salt thereof:

Compound (II):

E88. Any of embodiments 1-84, wherein said PDE10A inhibitor is MP-10 or a pharmaceutically acceptable salt thereof:

MP-10:

E89. Any of the preceding embodiments, wherein the PDE10A inhibitor is administered in a pharmaceutical composition.

E90. A PDE10A inhibitor for use in the treatment of persistent negative symptoms in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms. E91. A PDE10A inhibitor for use in treatment of prominent negative symptoms in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms.

E92. A PDE10A inhibitor for use in treatment of persistent prominent negative symptoms in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms.

E93. A PDE10A inhibitor for use in treatment of predominant negative symptoms in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms.

E94. A PDE10A inhibitor for use in treatment of persistent predominant negative symptoms in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms.

E95. A PDE10A inhibitor for use according to any of embodiments 90-94, wherein the negative symptoms are selected from the group consisting of: alogia, amotivation, anhedonia, asociality, emotional withdrawal, social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking, affective flattening, avolition, dysphoric mood, lack of insight, and demoralisation.

E96. A PDE10A inhibitor for use according to embodiment 95, wherein the negative symptoms are selected from the group consisting of: social withdrawal, anhedonia and avolition.

E97. A PDE10A inhibitor for use in treating cognitive impairments in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms.

E98. A PDE10A inhibitor for use according to embodiment 97, wherein the cognitive impairment is selected from the group consisting of: impaired executive functioning, impaired working memory and attention deficits. E99. A PDE10A inhibitor for use according to any of embodiments 90-98, wherein the clinical stable positive symptoms are defined by the positive symptoms not surpassing moderate severity.

E100. A PDE10A inhibitor for use according to embodiment 99, wherein the clinical stable positive symptoms are defined by a score of <4 out of score of 7 on each of the following PANSS items: Delusions (PI), Hallucinatory behaviour (P3), Suspiciousness/persecution (P6),

Uncooperativeness (G8), and Unusual thought content (G9).

E101. A PDE10A inhibitor for use according to either of embodiments 99-100, wherein the patient with clinical stable positive symptoms are defined by having had no acute exacerbation requiring hospitalization within the last 6 months.

E102. A PDE10A inhibitor for use according to any of embodiments 99-101, wherein the patient with clinical stable positive symptoms are defined by having had no acute exacerbation requiring change in antipsychotic medication within the last 6 months.

E103. A PDE10A inhibitor for use according to any of embodiments 90-102, wherein the negative symptoms are primary negative symptoms.

E104. A PDE10A inhibitor for use according to any of embodiments 90-103, wherein the patient suffers from deficit schizophrenia or residual schizophrenia.

E105. A PDE10A inhibitor for use according to any of embodiments 90-103, wherein the patient suffers from simple schizophrenia or simple type schizophrenia.

E106. A PDE10A inhibitor for use according to any of embodiments 90-103, wherein the patient suffers from schizotypal personality disorder or schizoaffective disorder.

E107. A PDE10A inhibitor for use according to any of embodiments 90-106, wherein the patient's negative symptoms are at least moderate in severity. E108. A PDE10A inhibitor for use according to embodiment 104, wherein the patient with negative symptoms are further characterized by having a PANSS Marder Negative Symptom Factor Score >20.

E109. A PDE10A inhibitor for use according to any of embodiments 90-108, wherein the patient to be treated has not previously been treated with an antipsychotic drug.

E110. A PDE10A inhibitor for use according to any of embodiments 90-108, wherein the patient to be treated is currently treated with an antipsychotic drug, and wherein the patient is switched to treatment with a PDE10A inhibitor administered as monotherapy.

Elll. A PDE10A inhibitor for use according to any of embodiments 90-110, wherein any positive symptoms remain clinically stable during the treatment with a PDE10A inhibitor administered as monotherapy.

E112. A PDE10A inhibitor for use in ameliorating negative symptoms and/or in a prophylactic treatment delaying the onset of psychosis in a patient displaying prodrome of schizophrenia.

E113. A PDE10A inhibitor for use according to any of embodiments 90-112, wherein said PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by the change in the relevant score on any clinically valid scale to assess such symptoms.

E114. A PDE10A inhibitor for use according to embodiment 113, wherein said PDE10A inhibitor is effective in treating the negative symptoms as quantified by a clinically relevant change in BNSS score.

E115. A PDE10A inhibitor for use according to embodiment 113, wherein said PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by a clinically relevant change in PANSS score. E116. A PDE10A inhibitor for use according to any of embodiments 90-115, wherein said PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions and the treatment effect has commenced within 24 weeks of regularly administration of said PDE10A inhibitor.

E117. A PDE10A inhibitor for use according to any of embodiments 90-116, wherein said PDE10A inhibitor is selected from the group consisting of compound (I), compound (II) and MP-10, or a pharmaceutically acceptable salt of any of said compounds:

MP-10:

Compound (1); Compound (SI):

E118. A PDE10A inhibitor for use according to embodiment 117, wherein said PDE10A inhibitor is compound (I) or a pharmaceutically acceptable salt thereof:

Compound (I):

E119. A PDE10A inhibitor for use according to embodiment 118, wherein said pharmaceutically acceptable salt is selected from the group comprising: the hemiadipate, hydrogen bromide, hydrogen chloride, dihydrogen phosphate, hydrogen sulphate, citrate, fumarate, hemifumarate, D-glucoronate, glutarate, 2-oxo-glutarate, L(-)-malate, maleate, malonate, mesylate, oxalate, hemi-succinate, L(+)-tartrate, and tosylate salt of Compound (I):

E120. A PDE10A inhibitor for use according to any of embodiments 90-119, wherein the PDE10A inhibitor is administered in a pharmaceutical composition.

E121. A PDE10A inhibitor for use according to any of embodiments 90-120, wherein the PDE10A inhibitor is administered by the oral route in a therapeutically effective amount.

E122. A method of treating persistent negative symptoms in a patient suffering from schizophrenia, comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to said patient as monotherapy and wherein said patient has clinically stable positive symptoms.

E123. A method of treating prominent negative symptoms in a patient suffering from schizophrenia, comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to said patient as monotherapy and wherein said patient has clinically stable positive symptoms.

E124. A method of treating persistent prominent negative symptoms in a patient suffering from schizophrenia, comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to said patient as monotherapy and wherein said patient has clinically stable positive symptoms.

E125. A method of treating predominant negative symptoms in a patient suffering from schizophrenia, comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to said patient as monotherapy and wherein said patient has clinically stable positive symptoms. E126. A method of treating persistent predominant negative symptoms in a patient suffering from schizophrenia, comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to said patient as monotherapy and wherein said patient has clinically stable positive symptoms.

E127. A method of treatment according to any of embodiments 122-126, wherein the negative symptoms are selected from the group consisting of: alogia, amotivation, anhedonia, asociality, emotional withdrawal, social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking, affective flattening, avolition, dysphoric mood, lack of insight, and demoralisation.

E128. A method of treatment according to embodiments 127, wherein the negative symptoms are selected from the group consisting of: social withdrawal, anhedonia and avolition.

E129. A method of treating cognitive impairments in a patient suffering from schizophrenia comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to said patient as monotherapy and wherein said patient has clinically stable positive symptoms.

E130. A method of treatment according to embodiment 129, wherein the cognitive impairment is selected from the group consisting of: impaired executive functioning, impaired working memory and attention deficits.

E131. A method of treatment according to any of embodiments 122-130, wherein the clinical stable positive symptoms are defined by the positive symptoms not surpassing moderate severity.

E132. A method of treatment according to embodiment 131, wherein the clinical stable positive symptoms are defined by a score of <4 out of score of 7 on each of the following PANSS items: Delusions (PI), Hallucinatory behaviour (P3), Suspiciousness/persecution (P6),

Uncooperativeness (G8), and Unusual thought content (G9). E133. A method of treatment according to either of embodiments 131-132, wherein said patient with clinical stable positive symptoms are defined by having had no acute exacerbation requiring hospitalization within the last 6 months.

E134. A method of treatment according to any of embodiments 131-133, wherein said patient with clinical stable positive symptoms are defined by having had no acute exacerbation requiring change in antipsychotic medication within the last 6 months.

E135. A method of treatment according to any of embodiments 122-134, wherein the negative symptoms are primary negative symptoms.

E136. A method of treatment according to any of embodiments 122-135, wherein said patient suffers from deficit schizophrenia or residual schizophrenia.

E137. A method of treatment according to any of embodiments 122-135, wherein said patient suffers from simple schizophrenia or simple type schizophrenia.

E138. A method of treatment according to any of embodiments 122-135, wherein said patient suffers from schizotypal personality disorder or schizoaffective disorder.

E139. A method of treatment according to any of embodiments 122-138, wherein said patient's negative symptoms are at least moderate in severity.

E140. A method of treatment according to embodiment 139, wherein said patient with negative symptoms are further characterized by having a PANSS Marder Negative Symptom Factor Score >20.

E141. A method of treatment according to any of embodiments 122-140, wherein said patient to be treated has not previously been treated with an antipsychotic drug. E142. A method of treatment according to any of embodiments 122-140, wherein said patient to be treated is currently treated with an antipsychotic drug, and wherein the patient is switched to treatment with a PDE10A inhibitor administered as monotherapy.

E143. A method of treatment according to any of embodiments 122-142, wherein any positive symptoms remain clinically stable during the treatment with a PDE10A inhibitor administered as monotherapy.

E144. A method of ameliorating negative symptoms and/or delaying the onset of psychosis in a patient displaying prodrome of schizophrenia comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to said patient as monotherapy and wherein said patient has clinically stable positive symptoms.

E145. A method of treatment according to any of embodiments 122-144, wherein said PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by the change in the relevant score on any clinically valid scale to assess such symptoms.

E146. A method of treatment according to embodiment 145, wherein said PDE10A inhibitor is effective in treating the negative symptoms as quantified by a clinically relevant change in BNSS score.

E147. A method of treatment according to embodiment 145, wherein said PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by a clinically relevant change in PANSS score.

E148. A method of treatment according to any of embodiments 122-147, wherein said PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions and the treatment effect has commenced within 24 weeks of regularly administration of said PDE10A inhibitor. E149. A method of treatment according to any of embodiments 122-148, wherein said PDE10A inhibitor is selected from the group consisting of compound (I), compound (II) and MP-10, or a pharmaceutically acceptable salt of any of said compounds:

MP-10:

Compound {!): Compound (II):

E150. A method of treatment according to embodiment 149, wherein said PDE10A inhibitor is compound (I) or a pharmaceutically acceptable salt thereof:

Compound (I):

E151. A method of treatment according to embodiment 150, wherein said pharmaceutically acceptable salt is selected from the group comprising: the hemiadipate, hydrogen bromide, hydrogen chloride, dihydrogen phosphate, hydrogen sulphate, citrate, fumarate, hemifumarate,

D-glucoronate, glutarate, 2-oxo-glutarate, L(-)-malate, maleate, malonate, mesylate, oxalate, hemi-succinate, L(+)-tartrate, and tosylate salt of Compound (I):

E152. A method of treatment according to any of embodiments 122-151, wherein said PDE10A inhibitor is administered in a pharmaceutical composition.

E153. A method of treatment according to any of embodiments 122-152, wherein said PDE10A inhibitor is administered by the oral route in a therapeutically effective amount.

E154. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment of persistent negative symptoms in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms.

E155. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment of prominent negative symptoms in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms.

E156. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment of persistent prominent negative symptoms in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms.

E157. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment of predominant negative symptoms in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms.

E158. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment of persistent predominant negative symptoms in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms. E159. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 154-159, wherein the negative symptoms are selected from the group consisting of: alogia, amotivation, anhedonia, asociality, emotional withdrawal, social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking, affective flattening, avolition, dysphoric mood, lack of insight, and demoralisation.

E160. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to embodiment 159, wherein the negative symptoms are selected from the group consisting of: social withdrawal, anhedonia and avolition.

E161. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment of cognitive impairments in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms.

E162. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to embodiment 161, wherein the cognitive impairment is selected from the group consisting of: impaired executive functioning, impaired working memory and attention deficits.

E163. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 154-162, wherein the clinical stable positive symptoms are defined by the positive symptoms not surpassing moderate severity.

E164. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to embodiment 163, wherein the clinical stable positive symptoms are defined by a score of <4 out of score of 7 on each of the following PANSS items: Delusions (PI), Hallucinatory behaviour (P3), Suspiciousness/persecution (P6), Uncooperativeness (G8), and Unusual thought content (G9).

E165. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to either of embodiments 163-164, wherein the patient with clinical stable positive symptoms are defined by having had no acute exacerbation requiring hospitalization within the last 6 months. E166. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 163-165, wherein the patient with clinical stable positive symptoms are defined by having had no acute exacerbation requiring change in antipsychotic medication within the last 6 months.

E167. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 154-166, wherein the negative symptoms are primary negative symptoms.

E168. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 154-167, wherein the patient suffers from deficit schizophrenia or residual schizophrenia.

E169. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 154-167, wherein the patient suffers from simple schizophrenia or simple type schizophrenia.

E170. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 154-167, wherein the patient suffers from schizotypal personality disorder or schizoaffective disorder.

E171. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 154-170, wherein the patient's negative symptoms are at least moderate in severity.

E172. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to embodiment 171, wherein the patient with negative symptoms are further characterized by having a PANSS Marder Negative Symptom Factor Score >20.

E173. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment use according to any of embodiments 154-172, wherein the patient to be treated has not previously been treated with an antipsychotic drug.

E174. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 154-173, wherein the patient to be treated is currently treated with an antipsychotic drug, and wherein the patient is switched to treatment with a PDE10A inhibitor administered as monotherapy.

E175. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 154-174, wherein any positive symptoms remain clinically stable during the treatment with a PDE10A inhibitor administered as monotherapy.

E176. Use of a PDE10A inhibitor in the manufacture of a medicament for ameliorating negative symptoms and/or for prophylactic treatment delaying the onset of psychosis in a patient displaying prodrome of schizophrenia.

E177. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 154-176, wherein the PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by the change in the relevant score on any clinically valid scale to assess such symptoms.

E178. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to embodiment 177, wherein said PDE10A inhibitor is effective in treating the negative symptoms as quantified by a clinically relevant change in BNSS score.

E179. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to embodiment 177, wherein said PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by a clinically relevant change in PANSS score.

E180. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 154-179, wherein the PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions and the treatment effect has commenced within 24 weeks of regularly administration of said PDE10A inhibitor.

E181. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 154-180, wherein said PDE10A inhibitor is selected from the group consisting of compound (I), compound (II) and MP-10, or a pharmaceutically acceptable salt of any of said compounds:

E182. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiment 181, wherein said PDE10A inhibitor is compound (I) or a pharmaceutically acceptable salt thereof:

Compound (I):

E183. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to embodiment 182, wherein said pharmaceutically acceptable salt is selected from the group comprising: the hemiadipate, hydrogen bromide, hydrogen chloride, dihydrogen phosphate, hydrogen sulphate, citrate, fumarate, hemifumarate, D-glucoronate, glutarate, 2-oxo-glutarate, L(-)-malate, maleate, malonate, mesylate, oxalate, hemi-succinate, L(+)-tartrate, and tosylate salt of Compound (I):

Compound (I):

E184. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 122-183, wherein said PDE10A inhibitor or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition.

E185. Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 154-184, wherein said PDE10A inhibitor is administered by the oral route in a therapeutically effective amount.

All references, including publications, patent applications and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety (to the maximum extent permitted by law).

Headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

The description herein of any aspect or aspect of the invention using terms such as "comprising", "having," "including" or "containing" with reference to an element or elements is intended to provide support for a similar aspect or aspect of the invention that "consists of", "consists essentially of" or "substantially comprises" that particular element or elements, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood as also describing a composition consisting of that element, unless otherwise stated or clearly contradicted by context).

The use of any and all examples, or exemplary language (including "for instance", "for example", "e.g.", "such as" and "as such") in the present specification is intended merely to better illuminate the invention and does not pose a limitation on the scope of invention unless otherwise indicated.

It should be understood that the various aspects, embodiments, implementations and features of the invention mentioned herein may be claimed separately, or in any combination. The present invention includes all modifications and equivalents of the subject-matter recited in the claims appended hereto, as permitted by applicable law.

The invention is further described by the following non-limiting Examples. EXPERIMENTAL SECTION

The examples provided below serve to facilitate a more complete understanding of the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only, since alternative methods can be utilized to obtain similar results. Three distinct PDE10A inhibitors were employed in the experimental section of the present application which are shown in table 1. It is shown in the assays mimicking strong positive symptoms (Conditioned Avoidance Response, example 1), negative symptoms (Social Interaction task, example 4A), and cognitive symptoms (novel object recognition task, example 5) that the results are similar for all exemplified PDE10A inhibitors despite of their structural differences. Table 1:

Example 1- Lack of PDE10A Efficacy in Conditioned Avoidance Response (CAR) in Rats in High Dopamine State:

In the CAR task, animals are trained to respond to a stimulus within a certain time by moving from one place to another (avoidance), all current antipsychotic agents produce a selective suppression of the avoidance response and the CAR paradigm is therefore considered a model for antipsychotic activity (Wadenberg, 2010, Current Pharmaceutical Design, 16(3), 358 - 370). PDE10A inhibitors are known to reduce this conditioned avoidance response and hence, expected to have effective antipsychotic activity Patients with exacerbated positive symptoms can be expected to have increased striatal dopamine levels and since the dopamine receptors regulate the dopamine signal by controlling cAMP synthesis and PDE10A regulates the gain of this signal by controlling cAMP degradation, the effect of PDE10A inhibition might be altered in conditions with increased striatal dopamine tonus, such as found in patients with strong positive symptoms.

To investigate this further the effect of PDE10A inhibition was tested in the CAR assay in rats that were co-dosed with a low dose of d-amphetamine (0.20-0.25 mg/kg) to induce a high dopamine state (figurel). This study confirms that PDE10A inhibition alone reduced CAR as anticipated. However, it is also shown that combining a low dose d-amphetamine with Compound (I) (0.3 to 3 mg/kg) (figure L4) or MP-10 (1- 10 mg/kg) (figure IB) respectively, clearly reduces the capacity of PDE10A inhibition to suppress the CAR, even at doses normally leading to full suppression (figure 1). This indicates that the presumed antipsychotic efficacy of PDE10A inhibitors as measured in the CAR assay are suppressed when the animals are administered a low dose of d-amphetamine to model the higher dopamine levels believed to be associated with strong positive symptoms.

Figure 1 shows the effect of PDE10A inhibitors in the Conditioned Avoidance Response (CAR) assay in Rats as further described in example 1. The compounds were tested alone and in combination with a low dose d-amphetamine to induce a h igh dopamine state. The efficacy was measured as the mean number of avoidances and results are depicted as mean +/- SEM. PDE10A inhibitors dosed alone reduced CAR as expected, but when combined with d-amphetamine, this effect was abolished. This suggests that the antipsychotic efficacy of PDE10A inhibitors is likely reduced in a high dopamine state.

A: Effect of Compound (I) alone and in combination with low dose d-amphetamine. Bars represent the following dose groups (left to right): 1) Vehicle; 2) d-amphetamine (0.2 mg/kg); 3) Compound (I) (0.6 mg/kg); 4) Compound (I) (0.3 mg/kg) + d-amphetamine (0.2 mg/kg); 5) Compound (I) (0.6 mg/kg) + d- amphetamine (0.2 mg/kg); and 6) Compound (I) (3.0 mg/kg) + d-amphetamine (0.2 mg/kg). ** p<0.01 compared to vehicle. ns= non-significant.

B: Effect of MP-10 alone and in combination with low dose d-amphetamine. Bars represent the following dose groups (left to right): 1) Vehicle; 2) d-amphetamine (0.25 mg/kg); 3) MP-10 (1 mg/kg); 4) MP-10 (10 mg/kg); 5) MP-10 (1 mg/kg) + d-amphetamine (0.25 mg/kg); 6) MP-10 (2.5mg/kg) + d-amphetamine (0.25 mg/kg); and 7) MP-10 (10 mg/kg) + d-amphetamine (0.25 mg/kg). *** p<0.001 compared to vehicle. ns= non-significant.

Example 2 - Effect of PDE10A inhibitors on Synaptic Transmission in Prefrontal Cortex:

Hypoactivity in the prefrontal cortex due to reduced cortical dopamine D1 receptor signalling has been hypothesized to underlie negative symptoms. Hence, if this activity can be increased/normalized by PDE10A inhibition, such inhibitors can be effective in treating negative symptoms. This capability was investigated by measuring the excitatory postsynaptic potential in brain slices from rat prefrontal cortex. To ensure that measurements were feasible, the level of cAMP was increased in all brain slices by incubation with forskolin and the ability of PDE10A inhibition to stimulate synaptic transmission was then evaluated by comparing with vehicle (figure 2).

The results show that PDE10A inhibition significantly increase the synaptic transmission in prefrontal cortex compared to vehicle (p<0.01). This result indicates that PDE10A inhibitors can be effective in treating negative symptoms by normalizing the hypoactivity in the prefrontal cortex (figure2).

Figure 2 shows the effect of PDE10A inhibition on synaptic transmission in brain slices from rat prefrontal cortex as further described in example 2. Negative symptoms and cognitive dysfunctions are believed to be associated with low dopamine activity in the prefrontal cortex, caused by reduced cortical dopamine D1 receptor signalling. This data show that PDE10A inhibition increase synaptic transmission in brain slices from rat prefrontal cortex, and hence, has potential to treat the associated negative and cognitive symptoms.

A: Effect of PDE10A inhibition on normalized field excitatory postsynaptic potential (fEPSP)s as a function of time (min). The brain slices from rat prefrontal were treated with either vehicle (DMSO) or PDE10A inhibitor and in addition forskolin was applied after 60 minutes of measurements to increase the cAMP tonus in the slices, which was otherwise low due to reduced input from other brain areas. The application of forskolin gave rise to an increase in fEPSP slope in control slices treated with vehicle (DMSO, white circles). However, in the brain slices treated with PDE10A inhibitor (Compound (I), grey circles, 100 nM) the fEPSP slope was increase even further.

B : Relative fEPSP slope (average 50-60 min after forskolin application). The fEPSP slope was significantly increased by 100 nM Compound (I) (grey bar, 128 ± 4.4 %, n = 15) when compared to vehicle (DMSO) controls (white bar, 115 ± 2.1 %, n = 17, ** p<0.01).

Example 3 - PDE10A inhibition Modulates cAMP in both Dopamine D1 and D2 Expressing Neurons of the Striatum:

To investigate if PDE10A inhibition could potentially modulate cAMP in both D1 and D2 expressing neurons, rats were dosed with Compound (I) (0.5 mg/kg) and lh later the brains were isolated for in situ hybridization analysis of c-Fos expression (figure 3). c-Fos is known to be regulated by cAMP and thus this peptide functions as an indirect marker for cAMP levels and thereby also PDE10A activity. It was seen that c-Fos was strongly upregulated in the striatum of Compound (l)-treated animals compared to vehicle-treated animals, and this was true for both Dl- and D2-expressing MSNs of the striatum. These findings indicate that PDE10A inhibition increases cAMP levels in both Dl-expressing neurons of the striatum similar to a Dl agonist and in D2 -expressing neurons of the striatum similar to a D2 antagonist. Dopamine Dl receptors in the striatum are relevant for reward processing, which is perturbed in patients with negative symptoms, hence these results further support that PDE10A inhibition might be effective in treating negative symptoms.

Figure 3 shows that PDE10A inhibition modulates cAMP in both dopamine Dl and D2 receptor expressing neurons of the striatum, which are both relevant to schizophrenia; Dopamine Dl receptors in the striatum are relevant for reward processing, which is perturbed in patients with negative symptoms, whereas Dopamine D2 receptor antagonism underlies the effect of current antipsychotics on positive symptoms of schizophrenia. PDE10A inhibition increase c-Fos expression in both Dl (Fig 3 A, black bars) and D2 (Fig 3 B, black bars) receptor expressing neurons compared to vehicle (white bars), **** p<0.0001 vs vehicle. C-Fos is an indirect marker of neuronal activity, known to be upregulated by cAMP, hence the data show that PDE10A inhibition increase cAMP levels in Dl expressing neurons, similar to a Dl agonist, and in D2 receptor expressing neurons similar to D2 antagonists.

Example 4 - In Vivo Pharmacology of PDE10A Inhibition Related to Negative Symptoms:

Modelling negative symptoms in animals are challenging due to the relatively poor understanding of the underlying pathophysiology of this symptom domain. Nonetheless, efforts have been made to develop appropriate paradigms for various negative symptoms of schizophrenia such as the social withdrawal model, which is believed to be a valid model for negative symptoms (Wilson and Koenig, 2014 Eur Neuropsychopharmacol., 24(5), 759-773). Other models to investigate important aspects of negative symptoms present in various psychiatric disorders (schizophrenia, depression etc.), such as anhedonia, have also been developed. In these models the amount of sucrose intake in rodents following chronic mild stress are believed to be a reliable and robust measure of anhedonic symptoms (Willner P., 2017, Neurobiol Stress, vol. 6, 68-77).

A. Social Interaction task in Phencyclidine (PCP)-treated Mice:

Social withdrawal is a core domain of negative symptomatology. This deficit in desire to have social contact can be measured in rodents using the social interaction paradigm, which assesses exploration and social behaviours (Sub-chronic administration of PCP in rodents has been shown to recapitulate physiological as well as behavioural alterations, including social interaction deficit (Janhunen et al 2015, Psychopharmacology (Berl)., 232(21-22): 4059-4083; Pedersen et al., 2014, Behav Brain Res., 273: 63-72).

The effects of Compound (I) (0.02 and 0.08 mg/kg) and MP-10 (0.1 mg/kg) on social interaction deficit elicited by sub-chronic administration of PCP were evaluated. This study revealed a significant effect of the treatments: Sub-chronic treatment with PCP (once daily for 14 days at a dose of 13 mg/kg) induced a deficit in social interaction compared to animals treated sub-chronically with vehicle. This deficit was counteracted by acute administration of both Compound (I) at 0.02 and 0.08 mg/kg and of MP-10 at 0.1 mg/kg (figure 4).

Figure 4 shows the effect of PDE10A inhibitors on social interaction deficit elicited by sub-chronic treatment with PCP as further described in example 4. Social withdrawal or asociality is a core domain of negative symptomatology in schizophrenia and in animal models PCP (administered once daily for 14 days at a dose of 13 mg/kg) can induce significant deficit in social interaction as measured by mean interaction time(s) and results are depicted as mean +/- SEM. These deficits in social interaction were counteracted by PDE10A inhibition and indicate that PDE10A inhibitors may be useful in the treatment of core domains of negative symptoms, such as social withdrawal.

A: Effect of Compound (I) on social interaction deficit elicited by sub-chronic treatment with PCP. Data showed a significant PCP-induced deficit in social interaction. Compound (I) reversed this deficit significantly. Dosing groups (left to right): 1) Vehicle treated control animals (no PCP treatment); 2) sub chronic treatment with PCP + vehicle; 3) sub-chronic treatment with PCP + Compound (I) 0.02 mg/kg; 4) sub-chronic treatment with PCP + Compound (I) 0.08 mg/kg. *p<0.05 compared to sub-chronic treatment with PCP + vehicle.

B : Effect of MP-10 on social interaction deficit elicited by sub-chronic treatment with PCP. Data showed a significant PCP-induced deficit in social interaction MP-10 reversed this PCP-induced social interaction deficit. Dosing groups (left to right): 1) Vehicle treated control animals (no PCP treatment); 2) sub-chronic treatment with PCP + vehicle; 3) sub-chronic treatment with PCP + MP-10 0.1 mg/kg; *p<0.05 and **p<0.01 compared to sub-chronic treatment with PCP + vehicle.

These findings indicate that PDE10A inhibition can attenuate social withdrawal, which is a core domain of negative symptoms. B. Sucrose Intake in Rats Subjected to Chronic Mild Stress:

The chronic mild stress (CMS) model can be used to assess stress-induced anhedonia, measured as intake of a 1% sucrose solution in rats subjected to chronic mild stress for 7 weeks. CMS will facilitate a reduction in sucrose intake due to the establishment of a state of anhedonia. In this model, Compound (I) rapidly reversed the anhedonic state and increased sucrose intake in the stressed groups (figure 5).

Figure 5 The chronic mild stress (CMS) model is used to assess stress-induced hedonic deficits, measured as intake of a 1% sucrose solution in rats subjected to CMS for 7 weeks. Chronic mild stress led to the expected reduction in sucrose and subsequent administration of a PDE10A inhibitor rapidly normalized the sucrose intake in a dose dependent manner. This data suggests that PDE10A inhibitors may be useful in the treatment of anhedonia. This assay is further described in example 4.

A: This graph shows the sucrose consumption in control animals (non -stressed animals) and the effect of Compound (I) (0-10 mg/kg, p.o) or vehicle (10% cremophor, 1 mL/kg) on this parameter. Dosing groups: Vehicle/cremophor (open circles); Compound (1) 0.1 mg/kg (open squares); Compound (I) 0.3 mg/kg (open triangles); Compound (I) 1.0 mg/kg (closed circles); Compound (I) 10 mg/kg (closed squares).

B: This graph shows the sucrose consumption in animals exposed to chronic mild stress and the effect of Compound (I) (0-10 mg/kg, p.o) or vehicle (10% cremophor, 1 mL/kg) on this parameter. Treatment commenced following 2 weeks of stress. Dosing groups: Vehicle/cremophor (open circles); Compound (I) 0.1 mg/kg (open squares); Compound (I) 0.3 mg/kg (open triangles); Compound (I) 1.0 mg/kg (closed circles); Compound (I) 10 mg/kg (closed squares). ***p<0.001 vs control vehicle group; #p<0.05 ##p<0.01 ###<0.001 vs Week 0.

This data show that Compound (I) could rapidly reverse stress-induced hedonic deficits in rats, which suggests a potential for beneficial effect on common negative symptoms, such as anhedonia.

Example 5 - In Vivo Pharmacology of PDE10A Inhibition Related to Cognitive Dysfunctions:

Novel object recognition (NOR) in rodents is analogous in some ways to human declarative (episodic) memory, one of the cognitive domains which are abnormal in schizophrenia. The NOR task is a test paradigm reflecting visual learning and recognition processing that has been compared to human cognitive tests, such as the visual paired comparison task (Rajagopal L. et al., 2014, Current Pharmaceutical Design, 20, 5104-5114). Sub-chronic administration of phencyclidine (subPCP), has been shown to induce a behavioural and neurobiological syndrome in rodents upon cessation of treatment that is similar to symptoms related to schizophrenia, including cognitive dysfunctions.

The vehicle-treated rats spent significantly more time exploring a novel object during the 3-minute test period compared to subPCP rats (figure 6). Animals that had received PCP for 7 days prior to testing spent approximately an equal amount of time exploring both a familiar and a novel object.

Administration of Compound (I) (0.1 and 0.3 mg/kg, orally) and Compound (II) (0.1 mg/kg) significantly attenuated this PCP-induced deficit in novel object exploration time at both doses tested. Thus, the chemically diverse Compound (I) and Compound (II) both attenuated deficits in a NOR cognition-related task in the subPCP rat model, indicating that PDE10A inhibition can treat cognitive dysfunctions.

Fig. 6 The novel object recognition (NOR) task in rats is an in vivo assay used to mimic cognitive impairments as further described in example 5. Sub-chronic administration of PCP induces a behavioural and neurobiological syndrome in rodents upon cessation of treatment that bears a remarkable similarity to some of the core symptoms in schizophrenic patients, including cognitive disruption. As expected vehicle-treated rats spent significantly more time exploring a novel object compared to a familiar object, which is the natural behavior of rodents. Whereas animals that has received PCP for 7 days prior to testing spent approximately an equal amount of time exploring a familiar and a novel object, which indicate a state of cognitive impairment. Administration of PDE10A inhibitors significantly attenuated the PCP- induced deficits in novel object exploration time, which demonstrate that PDE10A inhibitors might be useful in the treatment of cognitive dysfunction.

A: Effect of Compound (I) in the novel object recognition (NOR) task in rats. White bars represent the time spent exploring the novel object and the black bars represent time spent exploring the familiar object within a test period of 3 minutes. Dosing groups: 1) Vehicle+Vehicle (V+V) represent control animals that have been administered vehicle and not PCP during the 7 days prior to testing and on the day of testing they were also treated with vehicle prior to performing the NOR task; 2) PCP+Vehicle (PCP+V) represent animals that have been administered PCP for 7 days prior to testing and on the day of testing they were treated with vehicle prior to performing the NOR task; 3) PCP+0.1 mg/kg represent animals that have been administered PCP for 7 days prior to testing and on the day of testing they were treated with Compound (I) 0.1 mg/kg prior to performing the NOR task; 4) PCP+0.3 mg/kg represent animals that have been administered PCP for 7 days prior to testing and on the day of testing they were treated with Compound (I) 0.3 mg/kg prior to performing the NOR task. ** p<0.01 and *** p<0.001 for familiar (black bars) vs novel (white bars).

B: Effect of Compound (II) in the novel object recognition (NOR) task in rats. White bars represent the time spent exploring the novel object and the black bars represent time spent exploring the familiar object within a test period of 3 minutes. Dosing groups: 1) Vehicle+Vehicle (V+V) represent control animals that have been administered vehicle and not PCP during the 7 days prior to testing and on the day of testing they were also treated with vehicle prior to performing the NOR task; 2) PCP+Vehicle (PCP+V) represent animals that have been administered PCP for 7 days prior to testing and on the day of testing they were treated with vehicle prior to performing the NOR task; 3) PCP+0.03 mg/kg represent animals that have been administered PCP for 7 days prior to testing and on the day of testing they were treated with Compound (II) 0.03 mg/kg prior to performing the NOR task; 4) PCP+0.1 mg/kg represent animals that have been administered PCP for 7 days prior to testing and on the day of testing they were treated with Compound (II) 0.1 mg/kg prior to performing the NOR task. ** p<0.01 for familiar (black bars) vs novel (white bars).

Example 6 - Clinical Efficacy of PDE10A inhibitors

The clinical efficacy of the compound of the invention for treating negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in patients can be tested by conducting a randomized double blinded placebo-controlled study. Such study may include the evaluation of the efficacy of two fixed-flexible doses (1-2 mg and 3-4 mg per day) of the PDE10A inhibitor.

The primary outcome measures could be the change in negative symptoms from baseline to week 12 of the study when assessment of said negative symptoms are done on a valid rating scale, such as the PANSS Marder Negative Symptom Factor score or the Brief Negative Symptom Scale (BNSS). The secondary outcome measures could be the change in Personal and Social Performance (PSP) score, Positive and Negative Syndrome Scale (PANSS) total score, PANSS Marder Negative Symptom Factor score, PANSS Negative subscale score, Clinical Global Impression - Schizophrenia (CGI-SCH-S) negative symptoms score and/or Global Impression - Schizophrenia (CGI-SCH-DC) negative symptoms score between baseline and 12 weeks of treatment.

Patients to be included should correlate with the subpopulations of schizophrenia suitable to be treated with compounds of the invention as described herein above. Such patient may be diagnosed with schizophrenia and suffers from persistent prominent or persistent predominant negative symptoms. Further, the patient is in a clinically stable phase of schizophrenia and has not more than moderate severity on relevant positive symptoms, which may be selected from delusions, hallucinatory behavior, suspiciousness/persecution, uncooperativeness, unusual thought content and conceptual disorganization.

A positive response in treatment could e.g. be defined as at least 10, 20, 30 or 40% decrease in negative symptoms and/or cognitive impairments, when measured on a validated scale (such as BNSS total score or any of the other suitable scales, such as those mentioned herein above and in the description of the present invention), between baseline and 12 or 24 weeks of treatment or between treatment and placebo at 12 or 24 weeks.

A detailed clinical protocol may be designed as described below and study protocols NCT03793712 and NCT03929497 (hereby incorporated by reference in their entirety (to the maximum extent permitted by law)).

A study to evaluate the efficacy of 2 fixed-flexible doses of a PDE10A inhibitor on negative symptoms in patients with schizophrenia:

Study arms:

1. PDE10A inhibitor, low dose (1-2 mg/day), tablet, once daily, 12 or 24 weeks

2. PDE10A inhibitor, low dose (3-4 mg/day), tablet, once daily, 12 or 24 weeks 3. Placebo, tablet, once daily, 12 or 24 weeks Inclusion Criteria

The patient has schizophrenia, diagnosed according to DSM-5^® as confirmed by the Mini- International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorders Studies (MINI- Schz).

• The patient has been known to the site and treated by the site for at least the last 12 months prior to Screening Visit 1.

• The patient has suffered from persistent prominent negative symptoms for the last 6 months prior to the Screening Visit 1, in the opinion of the investigator and recorded in medical records. · The patient has been treated for schizophrenia with stable doses of an oral antipsychotic within the approved dose range and without any dose increase during the last 6 months prior to Screening Visit 1 (dose reductions are acceptable).

• The patient has had no psychiatric admissions/hospitalization due to a clinical deterioration during the last 6 months prior to Screening Visit 1, this excludes ambulatory visits to ask for advice from the psychiatry team.

• The patient is in a clinically stable phase of schizophrenia and has not more than moderate severity on relevant positive symptoms, that is a score of <4 (moderate) out of score of 7 on each of the following PANSS items: Delusions (PI), Hallucinatory behaviour (P3), Suspiciousness / persecution (P6), Uncooperativeness (G8), Unusual thought content (G9) at Screening Visit 1, Washout Visit(s), Screening Visit 2, and Baseline Visit and a score <5 on Conceptual disorganization (P2).

The patient currently has no clinically significant acute extrapyramidal side effects (acute EPS) or tardive dyskinesia (TD) based upon the protocol-specified clinical examination. • The patient has prominent negative symptoms as demonstrated by a PANSS Marder Negative Symptom Factor Score (NSFS) >20 at Screening Visit 1, Washout Visit(s) and Screening Visit 2. NSFS is the sum of scores of the following PANSS items: Blunted affect (Nl), Emotional withdrawal (N2), Poor rapport (N3), Passive/apathetic social withdrawal (N4), Lack of spontaneity & flow of conversation (N6), Motor retardation (G7) and Active social avoidance (G16).

• The patient has a Clinical Global Impression-Schizophrenia Severity of Illness (CGI-SCH-S) overall severity score <4 at Screening Visit 1.

The patient does not currently have a diagnosis of Major Depressive Disorder or have depressive symptoms rated with a total score >5 on the Calgary Depression Scale for Schizophrenia (CDSS). « The patient has no history of violent behaviour for the last 12 months prior to Screening Visit 1.

• The patient has a caregiver or an identified responsible person (for example, partner, family member, social worker, case worker, or nurse) considered reliable by the investigator in providing support to the patient to ensure compliance with study treatment, outpatient visits, and protocol procedures. Exclusion criteria

• The patient has had an acute exacerbation requiring hospitalization within the last 6 months prior to Screening Visit 1.

• The patient has had an acute exacerbation requiring change in antipsychotic medication (with reference to drug or dose) within the last 6 months prior to Screening Visit 1. · The patient has a current diagnosis or a history of substance use disorder according to DSM-5^® criteria within 6 months prior to Screening Visit 1 with the exception of tobacco, or mild cannabis or mild alcohol use disorder (occasional - but not weekly recreational cannabis use is acceptable). Patients with a positive drug screen test for opiates, methadone, cocaine, amphetamines [including ecstasy], barbiturates, verified by repeated testing, are excluded from the study. • The patient is at significant risk of harming himself/herself or others in the investigator's opinion.

• The patient has tested positive for hepatitis A virus antibody (anti-FIAV IgM), hepatitis B surface antigen (H BsAg), or hepatitis C virus antibody (anti-HCV). If the anti-FICV test result is positive, but acute/chronic infection is excluded with a negative FICV RNA test patient can be included in the study.

• The patient has tested positive for human immunodeficiency virus (HIV).

• The patient has a present condition that might compromise liver function (for example, alcohol abuse, hepatitis, hepatic insufficiency, cholestasis, haemachromatosis, deficit in alpha 1 antitrypsine, Wilson's Disease, autoimmune diseases, cirrhosis).

• The patient has any other disorder for which the treatment takes priority over treatment of schizophrenia or is likely to interfere with the study treatment or impair treatment compliance.

Primary Outcome Measures

• Change in Negative Symptom Scale (BNSS) total score [ Time Frame: from baseline to Week 12 or week 24]

The BNSS is a brief clinician rating scale, intended to measure negative symptoms. It consists of 13 items organized into 6 subscales: anhedonia, distress, asociality, avolition, blunted affect and alogia. The items score the impairment. Items 1 to 4 are rated from 0 (Normal) to 6 (Extremely severe) and items 5 to 13 are rated from 0 (No impairment) to 6 (Severe deficit). The BNSS total score is calculated by summing the 13 individual items; subscale scores are calculated by summing the individual items within each subscale. Users of the BNSS should have training in psychiatric interview techniques and have clinical experience working with patients with schizophrenia and related psychotic disorders. The BNSS total scores ranges from 0 to 78.

• Number of participants with Treatment-Emergent Adverse Events [ Time Frame: From baseline week 24 ]

Safety and Tolerability based on the safety assessments (clinical safety laboratory tests, vital signs, BMI, waist, weight, ECG parameters Secondary Outcome Measures

• Change in Personal and Social Performance (PSP) score [ Time Frame: from baseline to Week 12 or week 24]

The PSP is a clinician-rated scale designed and validated to measure a patient's current level of social functioning. The PSP consists of 4 items: socially useful activities (including work and study), personal and social relationships, self-care, and disturbing and aggressive behaviours. The 4 items are assessed on a 6- point scale, from absent to very severe. Based on these assessments and their combination, individual scores are converted into a global score ranging from 1 to 100.

• Change in Positive and Negative Syndrome Scale (PANSS) total score [ Time Frame: from baseline to Week 12 or week 24]

The PANSS is a clinician rated scale designed to measure severity of psychopathology in adult patients with schizophrenia, schizoaffective disorders and other psychotic disorders. It emphasizes positive and negative symptoms. The PANSS includes 3 sub-scales and 30 items. 7 items make up the positive scale (for example: delusions, conceptual disorganization and hallucinatory behaviour), 7 items make up the negative scale (for example: blunted affect, emotional withdrawal and poor rapport) and 16 items make up the general psychopathology scale (for example: somatic concern, anxiety and guilt feelings). Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). The PANSS total score is the sum of all items, and ranges from 30 to 210. Subscale scores are the sum of items within each subscale.

• Change in PANSS Marder Negative Symptom Factor score: negative symptoms [ Time Frame: from baseline to Week 12 or week 24]

The PANSS is a clinician rated scale designed to measure severity of psychopathology in adult patients with schizophrenia, schizoaffective disorders and other psychotic disorders. It emphasizes positive and negative symptoms. The PANSS includes 3 sub-scales and 30 items.

• Change in PANSS Negative subscale score [ Time Frame: from baseline to Week 12 or week 24]

• Change in Clinical Global Impression - Schizophrenia (CGI-SCH-S) negative symptoms score [ Time Frame: from baseline to Week 12 or week 24]

The CGI-SCH is a clinician-rated scale to assess global illness severity and degree of change in patients with schizophrenia. For both the global illness severity and degree of change, the CGI-SCH consists of four different groups of symptoms (positive, negative, cognitive and depressive) and the overall severity of the disorder. The CGI-SCH-S severity of illness category symptoms and overall severity are rated on a 7-point scale ranging from 1 (normal - not ill) to 7 (Among the most severely ill). For the first four ratings (positive, negative, depressive, and cognitive symptoms), the assessment should focus on the severity of symptoms only. Additionally, for 'overall severity' rating, both severity of symptoms and interference with functioning should be considered.

• Clinical Global Impression - Schizophrenia (CGI-SCFI-DC) negative symptoms score [ Time Frame: at Week 12 or week 24]

The CG l-SCH is a clinician-rated scale to assess global illness severity and degree of change in patients with schizophrenia. For both the global illness severity and degree of change, the CG l-SCH consists of four different groups of symptoms (positive, negative, cognitive and depressive) and the overall severity of the disorder. In the CGI-SCFI-DC degree of change category symptoms and overall severity are rated on a 7- point scale ranging from 1 (very much improved) to 7 (very much worse). Each single rating (conditions of severity and degree of improvement) and overall ratings of severity and improvement are scored independently and no total score is derived.

• CGI-SCFI-DC negative symptoms response [ Time Frame: at Week 12 or week 24]

The CG l-SCH is a clinician-rated scale to assess global illness severity and degree of change in patients with schizophrenia. For both the global illness severity and degree of change, the CG l-SCH consists of four different groups of symptoms (positive, negative, cognitive and depressive) and the overall severity of the disorder. In the CGI-SCFI-DC degree of change category symptoms and overall severity are rated on a 7- point scale ranging from 1 (very much improved) to 7 (very much worse). Each single rating (conditions of severity and degree of improvement) and overall ratings of severity and improvement are scored independently and no total score is derived. Response defined as CGI-SCFI-DC negative symptoms = 1 or 2

• BNSS response [ Time Frame: at Week 12 or week 24]

The BNSS is a brief clinician rating scale, intended to measure negative symptoms. It consists of 13 items organized into 6 subscales: anhedonia, distress, asociality, avolition, blunted affect and alogia. The items score the impairment. Items 1 to 4 are rated from 0 (Normal) to 6 (Extremely severe) and items 5 to 13 are rated from 0 (No impairment) to 6 (Severe deficit). The BNSS total score is calculated by summing the 13 individual items; subscale scores are calculated by summing the individual items within each subscale. Users of the BNSS should have training in psychiatric interview techniques and have clinical experience working with patients with schizophrenia and related psychotic disorders. The BNSS total scores ranges from 0 to 78. Response criteria defined as 20, 30 or 40% decrease in BNSS total score.

• Change in PANSS -Positive subscale score [ Time Frame: from baseline to Week 12 or week 24]

The PANSS is a clinician rated scale designed to measure severity of psychopathology in adult patients with schizophrenia, schizoaffective disorders and other psychotic disorders. It emphasizes positive and negative symptoms. The PANSS includes 3 sub-scales and 30 items

• Change in Clinical Global Impression - Schizophrenia (CGI-SCH-S) severity of illness overall severity score [ Time Frame: from baseline to Week 12 or week 24]

The CG l-SCH is a clinician-rated scale to assess global illness severity and degree of change in patients with schizophrenia. For both the global illness severity and degree of change, the CG l-SCH consists of four different groups of symptoms (positive, negative, cognitive and depressive) and the overall severity of the disorder. The CGI-SCH-S severity of illness category symptoms and overall severity are rated on a 7-point scale ranging from 1 (normal - not ill) to 7 (Among the most severely ill). For the first four ratings (positive, negative, depressive, and cognitive symptoms), the assessment should focus on the severity of symptoms only. Additionally, for 'overall severity' rating, both severity of symptoms and interference with functioning should be considered.

• Clinical Global Impression - Schizophrenia (CGI-SCH-DC) degree of change in overall severity score [ Time Frame: at Week 12 or week 24]

The CGI-SCH is a clinician-rated scale to assess global illness severity and degree of change in patients with schizophrenia. For both the global illness severity and degree of change, the CGI-SCH consists of four different groups of symptoms (positive, negative, cognitive and depressive) and the overall severity of the disorder. In the CGI-SCH-DC degree of change category symptoms and overall severity are rated on a 7- point scale ranging from 1 (very much improved) to 7 (very much worse). Each single rating (conditions of severity and degree of improvement) and overall ratings of severity and improvement are scored independently and no total score is derived.

• Change in Calgary Depression Scale for Schizophrenia (CDSS) total score [ Time Frame: from baseline to Week 12 or week 24]

The CDSS is a 9-item clinician rated scale specifically developed for the assessment of depression in patients with schizophrenia. The items on the CDSS are all typical depressive symptoms and do not appear to overlap with the negative symptoms of schizophrenia. All items are rated on a 4-point scale from 0 (absent) to 3 (severe).

Claims

CLAIMS:

1. A PDE10A inhibitor for use in the treatment of negative symptoms in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein said patient has clinically stable positive symptoms.

2. The PDE10A inhibitor for use according to claim 1, wherein the negative symptoms are persistent negative symptoms.

3. The PDE10A inhibitor for use according to claim 1, wherein the negative symptoms are prominent negative symptoms.

4. The PDE10A inhibitor for use according to claim 1, wherein the negative symptoms are persistent prominent negative symptoms.

5. The PDE10A inhibitor for use according to claim 1, wherein the negative symptoms are predominant negative symptoms.

6. The PDE10A inhibitor for use according to claim 1, wherein the negative symptoms are persistent predominant negative symptoms.

7. The PDE10A inhibitor for use according to any of claims 1-6, wherein the negative symptoms are selected from the group consisting of: alogia, amotivation, anhedonia, asociality, emotional withdrawal, social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking, affective flattening, avolition, dysphoric mood, lack of insight, and demoralisation.

8. The PDE10A inhibitor for use according to claim 7, wherein the negative symptoms are selected from the group consisting of: social withdrawal, anhedonia and avolition.

9. A PDE10A inhibitor for use in treating cognitive impairments in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein said patient has clinically stable positive symptoms.

10. The PDE10A inhibitor for use according to claim 9, wherein the cognitive impairment is selected from the group consisting of: impaired executive functioning, impaired working memory and attention deficits.

11. The PDE10A inhibitor for use according to any of claims 1-10, wherein the clinical stable positive symptoms are defined by the positive symptoms not surpassing moderate severity.

12. The PDE10A inhibitor for use according to any of claims 1-11, wherein the clinical stable positive symptoms are defined by a score of <4 out of score of 7 on each of the following PANSS items: Delusions (PI), Hallucinatory behaviour (P3), Suspiciousness/persecution (P6),

Uncooperativeness (G8), and Unusual thought content (G9).

13. The PDE10A inhibitor for use according to any of claims 1-12, wherein said patient with clinical stable positive symptoms are defined by having had no acute exacerbation requiring hospitalization within the last 6 months.

14. The PDE10A inhibitor for use according to any of claims 1-13, wherein said patient with clinical stable positive symptoms are defined by having had no acute exacerbation requiring change in antipsychotic medication within the last 6 months.

15. The PDE10A inhibitor for use according to any of claims 1-8 and 11-14, wherein the negative symptoms are primary negative symptoms.

16. The PDE10A inhibitor for use according to any of claims 1-15, wherein said patient suffers from deficit schizophrenia or residual schizophrenia.

17. The PDE10A inhibitor for use according to any of claims 1-15, wherein said patient suffers from simple schizophrenia or simple type schizophrenia.

18. The PDE10A inhibitor for use according to any of claims 1-15, wherein said patient suffers from schizotypal personality disorder or schizoaffective disorder.

19. The PDE10A inhibitor for use according to any of claims 1-8 and 11-18, wherein said patient's negative symptoms are at least moderate in severity.

20. The PDE10A inhibitor for use according to any of claims 1-8 and 11-19, wherein said patient with negative symptoms are further characterized by having a PANSS Marder Negative Symptom Factor Score >20.

21. The PDE10A inhibitor for use according to any of claims 1-20, wherein said patient to be treated has not previously been treated with an antipsychotic drug.

22. The PDE10A inhibitor for use according to any of claims 1-20, wherein said patient to be treated is currently treated with an antipsychotic drug, and wherein said patient is switched to treatment with said PDE10A inhibitor administered as monotherapy.

23. The PDE10A inhibitor for use according to any of claims 1-22, wherein any positive symptoms remain clinically stable during the treatment with said PDE10A inhibitor administered as monotherapy.

24. A PDE10A inhibitor for use in ameliorating negative symptoms and/or in a prophylactic treatment delaying the onset of psychosis in a patient displaying prodrome of schizophrenia.

25. The PDE10A inhibitor for use according to any of claims 1-24, wherein said PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by the change in the relevant score on any clinically valid scale to assess such symptoms.

26. The PDE10A inhibitor for use according to claim 25, wherein said PDE10A inhibitor is effective in treating the negative symptoms as quantified by a clinically relevant change in BNSS score.

27. The PDE10A inhibitor for use according to claim 25, wherein said PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by a clinically relevant change in PANSS score.

28. The PDE10A inhibitor for use according to any of claims 1-27, wherein said PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions and the treatment effect has commenced within a bout 24 weeks of regularly administration of said PDE10A inhibitor.

29. The PDE10A inhibitor for use according to any of claims 1-28, wherein said PDE10A inhibitor is selected from the group consisting of compound (I), compound (II) and MP-10, or a pharmaceutically acceptable salt of any of said compounds:

MP-10:

Compound (l); Compound (SI):

30. The PDE10A inhibitor for use according to claim 29, wherein said PDE10A inhibitor is compound (I) or a pharmaceutically acceptable salt thereof:

Compound (I):

31. The PDE10A inhibitor for use according to claim 30, wherein said pharmaceutically acceptable salt is selected from the group comprising: the hemiadipate, hydrogen bromide, hydrogen chloride, dihydrogen phosphate, hydrogen sulphate, citrate, fumarate, hemifumarate, D-glucoronate, glutarate, 2-oxo-glutarate, L(-)-malate, maleate, malonate, mesylate, oxalate, hemi-succinate, L(+)-tartrate, and tosylate salt of Compound (I):

32. The PDE10A inhibitor for use according to claim 29, wherein said PDE10A inhibitor is compound (II) or a pharmaceutically acceptable salt thereof:

Compound (II):

33. The PDE10A inhibitor for use according to claim 29, wherein said PDE10A inhibitor is MP-10 or a pharmaceutically acceptable salt thereof:

MP-10:

34. The PDE10A inhibitor for use according to any of claims 1-33, wherein said PDE10A inhibitor is administered in a pharmaceutical composition.

35. The PDE10A inhibitor for use according to any of claims 1-34, wherein said PDE10A inhibitor is administered by the oral route in a therapeutically effective amount.