Enhancing cAMP signaling as a combination drug strategy for the treatment of depression and related conditions

Abstract

The present invention relates to the use of a phosphodiesterase 4 (PDE4) inhibitor in combination with one or more of a 5-HT4 agonist, an H3 antagonist or inverse agonist, a nicotinic alpha7 receptor agonist, a beta3 adrenergic agonist or a TAAR1 agonist for treating psychiatric and neurological disorders in which depression, anhedonia, motivation-related or cognitive-related dysfunction is present (e.g. major depressive disorder, bipolar I disorder, post-traumatic stress disorder, addiction, anhedonia, or motivation-related aspects of schizophrenia (e.g. negative symptoms and cognitive symptoms), and Parkinson's disease (e.g. non-motor features such as depression, apathy and cognitive impairment).

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Application No. 63 / 199,728, filed January 20, 2021, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to the use of a phosphodiesterase 4 inhibitor in combination with one or more of a 5-HT4 agonist, an H3 antagonist or inverse agonist, a nicotinic alpha7 receptor agonist, a beta3 adrenergic agonist or a TAAR1 agonist for treating psychiatric and neurological disorders in which depression, anhedonia, motivation-related or cognitive-related dysfunction is present (e.g. major depressive disorder, bipolar I disorder, post-traumatic stress disorder, addiction, anhedonia, or motivation-related aspects of schizophrenia (e.g. negative symptoms and cognitive symptoms), and Parkinson's disease (e.g. non-motor features such as depression, apathy and / or cognitive impairment). [Background technology]

[0003] There are many psychiatric and neurological disorders in which depressive symptoms, lack of pleasure experiences (anhedonia), or motivation-related and / or cognitive-related disorders are present. These are often difficult-to-treat features of these disorders and predict a chronic, disabling disease course. Given that only 43% of depressed patients achieve sustained remission over a one-year period, even with the most comprehensive treatment plans (1), and this is the disorder for which the greatest number of treatment options exist, there is a need for more effective treatments in depression and in diseases or disorders with elements of depression, anhedonia, motivational disorders, and / or cognitive disorders. Psychiatric and neurological conditions characterized by symptoms of depression, anhedonia, motivational disorders, and / or cognitive disorders include major depressive disorder, bipolar depression (e.g., bipolar I disorder), post-traumatic stress disorder (PTSD), addiction, schizophrenia (e.g., negative symptoms), and Parkinson's disease (e.g., non-motor features such as depression, apathy, and cognitive disorders).

[0004] Importantly, these various depression-related symptoms or dysfunctional areas may co-occur and be functionally related. For example, patients with major depression may report depressed mood, anhedonia, lack of motivation, and cognitive impairment. Similarly, patients diagnosed with other conditions, such as bipolar depression, post-traumatic stress disorder, or addiction, that may co-occur with similar dysfunction, may report the same symptoms. Schizophrenia is often thought of in terms of prominent hallucinations and delusions, but negative symptoms such as depression and related cognitive symptoms often contribute significantly to long-term disability and impairment. Similarly, Parkinson's disease is associated with prominent motor dysfunction, but is also often associated with highly disabling non-motor features such as depression, apathy, and cognitive impairment. Thus, a treatment approach that encompasses these multiple related functional systems may be important for any of these clinical conditions and may be equally applicable across them.

[0005] Preclinical and clinical studies suggest that cyclic adenosine monophosphate (cAMP) signaling is important for depression or aspects of its symptoms such as anhedonia, motivational dysfunction, and cognitive impairment. For example, PET imaging of phosphodiesterase 4 (PDE4) binding and activity, one of the key enzymes that breaks down cAMP, showed reduced PDE4 activity in patients with major depression (2). This has been interpreted as a decrease in cAMP signaling at baseline, which increases after antidepressant treatment, given the close relationship between cAMP levels and downstream effects on protein kinase A activity and the resulting phosphorylation and enzyme activity levels of PDE4 (as an autoregulatory functional feedback loop). Consistent with this view, injection of an inhibitor of protein kinase A into the brain reduced PET-measured PDE4 levels, whereas injection of a protein kinase A activator increased PET-measured PDE4 levels (3). Postmortem studies have found changes in other components of cAMP-related signaling, such as adenylyl cyclase levels (4-6). A role for dysfunction in cAMP signaling has also been proposed to be observed in other disorders in which depression or cognition-related dysfunction is present, such as bipolar disorder and schizophrenia (27-28).

[0006] Given these findings, one of the main ways to pharmacologically increase cAMP signaling has been to inhibit its degradation, focusing primarily on the role of PDE4. This protein is present throughout much of the nervous system (as well as various peripheral tissues), and its manipulation may have therapeutic benefits. Mice lacking subtypes of the PDE4 protein display both antidepressant-like and pro-cognitive phenotypes (7). Similarly, mice treated with rolipram, a standard inhibitor of PDE4, display similar antidepressant and pro-cognitive phenotypes (7). The utility of PDE4 inhibitors for the treatment of depression in humans is far from clear. To date, there has not been a single placebo-controlled study of PDE4 inhibitors in patients with depression. Similarly, there are no placebo-controlled studies of PDE4 inhibitors in other psychiatric disorders where depression, anhedonia, motivation-related or cognitive-related dysfunction are present (e.g., major depressive disorder, bipolar I disorder, post-traumatic stress disorder, addiction and anhedonia, or motivation-related aspects of schizophrenia (e.g., negative and cognitive symptoms)). There have been a number of small clinical trials in depression comparing the PDE4 rolipram with tricyclic antidepressant (TCA) drugs (8-10). In each of these studies, rolipram produced more improvement in depression than the TCA drugs, but in some cases produced significantly worse outcomes (9,10). Furthermore, even if the results for rolipram and the TCAs were statistically indistinguishable, the study results were too insufficient to prove noninferiority with statistical confidence. Roflumilast, another PDE4 inhibitor developed for chronic obstructive pulmonary disease, can also reach the brain and has been found to have cognitive-promoting effects largely consistent with studies of PDE4 inhibitors in animals (11-13), but there is no evidence of an antidepressant effect.

[0007] Despite the promise of the therapeutic potential of PDE4 inhibitors for depression and related conditions, they have been hampered by their limited therapeutic index due to side effects such as nausea and vomiting that necessitate dose-limiting effects. In fact, this limitation is severe enough to affect all clinically tested PDE4 inhibitors, occurring at relatively low doses (relative to target occupancy) such that the final range between ineffectiveness and intolerance is too narrow for the drug to be meaningfully effective for use in treating neuropsychiatric conditions. In other words, part of the power and promise of promoting cAMP signaling is that this second messenger is used throughout the brain and thus may ameliorate many aspects of neuropsychiatric disorders. However, this advantage is also a major drawback, as cAMP in areas such as the area postrema of the brainstem also mediates the emetic effects of PDE4 inhibitors (14). Thus far, PDE4 inhibitors have not been used to achieve robust increases in cAMP signaling in parts of the brain important for depression and related conditions (e.g., frontal cortex, hippocampus, and striatum), but have avoided doing so in areas that cause emesis, such as the area postrema. As a result, several development programs for brain-directed PDE4 inhibitors have been discontinued by pharmaceutical companies.

[0008] The main proposal for how the potential of PDE4 inhibition could be realized, i.e., with minimal substantial side effects, is that new drugs could be designed to inhibit specific isoforms of the protein that are more important for therapeutic potential than for side effects (15, 16). However, to do so would require that both different isoforms have functions that can be so dissociated or that small molecule inhibitors could selectively target PDE4 in specific brain sites. To date, no such drugs have been identified or advanced to human testing. In the present invention, we address this problem from a different perspective and detail a novel solution. Summary of the Invention

[0009] One embodiment of the present invention is a pharmaceutical composition (e.g., an oral composition such as an oral tablet or oral liquid) comprising a PDE4 inhibitor (e.g., roflumilast, an N-oxide thereof, or a pharma- ceutically acceptable salt thereof) and at least one 5-HT4 agonist, H3 antagonist or inverse agonist, nicotinic α7 receptor agonist, β3 adrenergic agonist, or TAAR1 agonist.

[0010] The composition may comprise (a) a PDE4 inhibitor and (b) a 5-HT4 agonist. In one embodiment, the composition comprises (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof, and (b) prucalopride or a pharma- ceutically acceptable salt thereof (e.g., prucalopride succinate). For example, the composition may comprise (a) about 100 to about 500 mcg of roflumilast or an equivalent pharma- ceutically acceptable salt of roflumilast, and (b) about 0.25 to about 4 mg of prucalopride or an equivalent pharma- ceutically acceptable salt of prucalopride (e.g., prucalopride succinate). In another embodiment, the composition comprises (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof, and (b) capeserode or a pharma- ceutically acceptable salt thereof (e.g., capeserode hydrochloride). For example, the composition may contain (a) about 100 to about 500 mcg of roflumilast or an equivalent pharma- ceutically acceptable salt of roflumilast, and (b) about 1 μg to about 10 mg of capeserode or an equivalent pharma- ceutically acceptable salt of capeserode (e.g., capeserode hydrochloride).

[0011] In another embodiment, the composition comprises (a) a PDE4 inhibitor and (b) an H3 antagonist or inverse agonist. In one embodiment, the composition comprises (a) roflumilast, an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, and (b) pitolisant or a pharma- ceutically acceptable salt thereof (e.g., pitolisant hydrochloride). For example, the composition may comprise (a) about 100 to about 500 mcg of roflumilast or an equivalent pharma- ceutically acceptable salt of roflumilast, and (b) an amount of pitolisant or a pharma- ceutically acceptable salt thereof (e.g., pitolisant hydrochloride) equivalent to about 2 to about 40 mg of pitolisant hydrochloride. In another embodiment, the composition comprises (a) roflumilast, an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, and (b) iludavisant or a pharma- ceutically acceptable salt thereof (e.g., iludavisant hydrochloride). For example, the composition may contain (a) about 100 to about 500 mcg of roflumilast or an equivalent pharma- ceutically acceptable salt of roflumilast, and (b) an amount of iludabisant or a pharma- ceutically acceptable salt thereof (e.g., iludabisant hydrochloride) equivalent to about 1 to about 500 μg of iludabisant hydrochloride.

[0012] In yet another embodiment, the composition comprises (a) a PDE4 inhibitor and (b) a nicotinic α7 receptor agonist. In one embodiment, the composition comprises (a) roflumilast, an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, and (b) varenicline or a pharma- ceutically acceptable salt thereof. For example, the composition may comprise (a) about 100 to about 500 mcg of roflumilast or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast, and (b) about 0.25 to about 3 mg of varenicline or an equivalent amount of a pharma- ceutically acceptable salt thereof (e.g., varenicline tartrate).

[0013] In yet another embodiment, the composition comprises (a) a PDE4 inhibitor and (b) a β3 adrenergic agonist. In one embodiment, the composition comprises (a) roflumilast, an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, and (b) amibegron or a pharma- ceutically acceptable salt thereof. For example, the composition may comprise (a) about 100 to about 500 mcg of roflumilast or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast, and (b) about 100 to about 1400 mg of amibegron or an equivalent amount of a pharma- ceutically acceptable salt thereof (e.g., amibegron hydrochloride).

[0014] In yet another embodiment, the composition comprises (a) a PDE4 inhibitor and (b) a TAAR1 agonist. In one embodiment, the composition comprises (a) roflumilast, an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, and (b) urotaronto (SEP-363856) or a pharma- ceutically acceptable salt thereof. For example, the composition may comprise (a) about 100 to about 500 mcg of roflumilast or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast, and (b) about 5 to about 200 mg of urotaronto (SEP-363856) or an equivalent amount of a pharma- ceutically acceptable salt thereof. In another embodiment, the composition comprises (a) roflumilast, an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, and (b) ralmitaronto (RO6889450) or a pharma- ceutically acceptable salt thereof. For example, the composition comprises: (a) about 100 to about 500 mcg of roflumilast or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast; and (b) about 5 to about 300 mg of ralmitront (RO6889450) or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0015] In any of the embodiments described herein, the pharmaceutical composition may contain a sub-emetic amount of component (a) (a PDE4 inhibitor).

[0016] In any of the embodiments described herein, the pharmaceutical composition may comprise a sub-emetic amount of component (a) and effective amounts of components (a) and (b) together to treat an intended disorder, such as (a) depression (e.g., major depressive disorder or bipolar I disorder), (b) a psychiatric or neurological disorder in which anhedonia, motivation-related or cognitive-related dysfunction is present, or (c) one or more symptoms associated with depression, anhedonia, or motivation-related or cognitive-related dysfunction.

[0017] In any of the embodiments described herein, the pharmaceutical composition may contain an effective amount of the recited components (e.g., components (a) and (b)) to increase cAMP signaling.

[0018] Another embodiment is a method for treating (a) depression (e.g., major depressive disorder or bipolar I disorder), (b) psychiatric or neurological disorder in which anhedonia, motivation-related or cognitive-related dysfunction exists, or (c) one or more symptoms related to depression, anhedonia, or motivation-related or cognitive-related dysfunction in a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition of the present invention.In one embodiment, an effective amount of the pharmaceutical composition is administered to increase cAMP signaling.The psychiatric or neurological disorder may be post-traumatic stress disorder (PTSD), schizophrenia, addiction, or Parkinson's disease.

[0019] Yet another embodiment is a method for treating (a) depression (e.g. major depressive disorder or bipolar I disorder), (b) psychiatric or neurological disorder with anhedonia, motivation-related or cognitive-related dysfunction, or (c) one or more symptoms related to depression, anhedonia, or motivation-related or cognitive-related dysfunction in a subject in need thereof, comprising administering to the subject an effective amount of a PDE4 inhibitor (e.g. roflumilast, its N-oxide, or a pharmaceutical agent), and at least one of a 5-HT4 agonist, an H3 antagonist or inverse agonist, a nicotinic α7 receptor agonist, a β3 adrenergic agonist, or a TAAR1 agonist.The psychiatric or neurological disorder can be post-traumatic stress disorder (PTSD), schizophrenia, addiction, or Parkinson's disease.

[0020] In one embodiment, the method comprises administering an effective amount of (a) a PDE4 inhibitor and (b) a 5-HT4 agonist. In one preferred embodiment, the method comprises administering an effective amount of (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof, and (b) prucalopride or a pharma- ceutically acceptable salt thereof (e.g., prucalopride succinate). For example, the method may comprise administering (a) about 100 to about 500 mcg of roflumilast or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast per day, and (b) about 0.25 to about 4 mg of prucalopride or an equivalent amount of a pharma- ceutically acceptable salt of prucalopride (e.g., prucalopride succinate). In another preferred embodiment, the method includes administering (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof, and (b) capeserode or a pharma- ceutically acceptable salt thereof (e.g., capeserode hydrochloride). For example, the method may include administering (a) about 100 to about 500 mcg of roflumilast or an equivalent pharma- ceutically acceptable salt of roflumilast per day, and (b) about 1 μg to about 10 mg of capeserode or an equivalent pharma- ceutically acceptable salt of capeserode (e.g., capeserode hydrochloride) per day.

[0021] In another embodiment, the method comprises administering an effective amount of (a) a PDE4 inhibitor and (b) an H3 antagonist or inverse agonist. In one preferred embodiment, the composition comprises administering an effective amount of (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof, and (b) pitolisant or a pharma- ceutically acceptable salt thereof (e.g., pitolisant hydrochloride). For example, the method may comprise administering (a) about 100 to about 500 mcg of roflumilast or an equivalent pharma- ceutically acceptable salt of roflumilast per day, and (b) an amount of pitolisant or a pharma- ceutically acceptable salt thereof (e.g., pitolisant hydrochloride) equivalent to about 2 to about 40 mg of pitolisant hydrochloride per day. In another preferred embodiment, the composition comprises administering an effective amount of (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof, and (b) irudavisant or a pharma- ceutically acceptable salt thereof (e.g., irudavisant hydrochloride). For example, the method may comprise administering (a) about 100 to about 500 mcg of roflumilast or an equivalent pharma- ceutically acceptable salt of roflumilast per day, and (b) an amount of irudavisant or a pharma- ceutically acceptable salt thereof (e.g., irudavisant hydrochloride) equivalent to about 1 μg to about 500 μg of irudavisant hydrochloride per day.

[0022] In yet another embodiment, the method comprises administering an effective amount of (a) a PDE4 inhibitor and (b) a nicotinic α7 receptor agonist. In one preferred embodiment, the composition comprises administering an effective amount of (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof, and (b) varenicline or a pharma- ceutically acceptable salt thereof (e.g., varenicline tartrate). For example, the method may comprise administering (a) about 100 to about 500 mcg of roflumilast or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast per day, and (b) about 0.25 to about 3 mg of varenicline or an equivalent amount of a pharma- ceutically acceptable salt thereof (e.g., varenicline tartrate) per day.

[0023] In yet another embodiment, the method comprises administering an effective amount of (a) a PDE4 inhibitor and (b) a β3 adrenergic agonist. In one preferred embodiment, the composition comprises administering an effective amount of (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof, and (b) amibegron or a pharma- ceutically acceptable salt thereof (e.g., amibegron hydrochloride). For example, the method may comprise administering (a) about 100 to about 500 mcg of roflumilast or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast per day, and (b) about 100 to about 1400 mg of amibegron or an equivalent amount of a pharma- ceutically acceptable salt thereof (e.g., amibegron hydrochloride) per day.

[0024] In yet another embodiment, the method comprises administering an effective amount of (a) a PDE4 inhibitor and (b) a TAAR-1 agonist. In one preferred embodiment, the composition comprises administering (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof, and (b) urotaronto (SEP-363856) or a pharma- ceutically acceptable salt thereof. For example, the method may comprise administering (a) about 100 to about 500 mcg of roflumilast or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast per day, and (b) about 5 to about 200 mg of urotaronto (SEP-363856) or an equivalent amount of a pharma- ceutically acceptable salt thereof per day. In another preferred embodiment, the composition comprises administering an effective amount of (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof, and (b) ralmitaronto (RO6889450) or a pharma- ceutically acceptable salt thereof. For example, the method may comprise administering (a) about 100 to about 500 mcg of roflumilast or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast per day, and (b) about 5 to about 300 mg of ralmitront (RO6889450) or an equivalent amount of a pharma- ceutically acceptable salt thereof per day.

[0025] In another embodiment, the methods described herein may comprise administering an effective amount of the recited components (e.g., components (a) and (b)) to increase cAMP signaling.

[0026] The preferred PDE4 inhibitor in any of the compositions or methods described herein is roflumilast, AVE8112 (4-(cyclopropylmethoxy)-N-(3,5-dichloro-1-oxidopyridin-4-yl)-5-methoxypyridine-2-carboxamide), MEM1414, MEM1917, apremilast, cilomilast, crisaborole, ibudilast, luteolin, mesembrenone, piclamilast, rolipram, chlorvipram, GSK-256066, E-6005, MK-0873, BPN14770, HT-0712, or a pharmaceutically acceptable salt thereof.Other suitable PDE4 inhibitors include those disclosed in International Publication Nos. WO95 / 04545 and WO2008 / 145840, which are incorporated herein by reference.

[0027] Preferred 5-HT4 agonists in any of the compositions or methods described herein are prucalopride, cisapride, BIMU-8, CJ-033466, ML-10302, mosapride, renzapride, RS-67506, RS67333, SL65.0155 (capeserod), tegaserod, zacopride, metoclopramide, spride, or a pharma- ceutically acceptable salt thereof (e.g., prucalopride succinate).

[0028] A preferred H3 antagonist or H3 inverse agonist in any of the compositions or methods described herein is pitolisant, ABT-28, BF2.649, CEP-26401 (iludavisant), GSK-189254, GSK-239512, MK-0249, PF-3654746, or a pharma- ceutically acceptable salt thereof (e.g., pitolisant hydrochloride).

[0029] Preferred nicotinic alpha7 receptor agonists for the compositions and methods described herein are varenicline, tilorone, A-582941, AR-R17779, TC-1698, bradanicline, ensenicline, GTS-21, PHA-543613, PNU-292987, PHA-709829, SSR-180711, tropisetron, WAY-317538, anabasine, epiboxidine, PNU-120596, NS-1738, AVL-3288, A867744, ivermectin, BNC210, or a pharma- ceutically acceptable salt thereof (e.g., varenicline tartrate).

[0030] Preferred TAAR1 agonists for the compositions and methods described herein are urotalont (SEP-363856), larmitalont (RO6889450), RO5166017, RO5256390, RO5203648, RO5263397, tyramine, amphetamine, methamphetamine, 3,4-methylenedioxy-methamphetamine (MDMA), or a pharma- ceutically acceptable salt thereof. [Brief description of the drawings]

[0031] [Figure 1] Included are schematics comparing (A) desirable complementary exposures for drug combinations with (B) drug targets that do not overlap with disease modules, or (C) drug targets that overlap with disease modules and each other. Complementary exposures mean that each drug module is in close proximity to a different part of the disease module (and furthermore, the drug modules do not overlap with each other). [Diagram 2]Table 1 shows the distance and proximity of specific drugs to specific disease and cognitive modules. Modules targeted by drugs in combinations are significantly closer to disease and cognitive modules than randomly selected modules of similar size. For all drugs except β3 adrenergic agonists, we used a network consisting of direct targets and additional genes whose expression is perturbed upon treatment of neurons or neural progenitor cells with the drug. For β3 adrenergic agonists, only direct targets were used due to the lack of gene expression data. In this table, negative Z scores represent statistically significant results, as assessed by permutation tests. [Diagram 3] Table 2 shows that the modules targeted by drugs in the combinations are complementary to each other in the disease and cognitive modules. For all drug combinations except PDE4 inhibitor + β3 adrenergic agonist, we used a network consisting of the direct targets plus additional genes whose expression is perturbed upon treatment of neurons or neural precursor cells with the drug. For the PDE4 inhibitor + β3 adrenergic agonist combination, only the direct targets were used due to lack of gene expression data. Positive separation values ​​indicate that the two drug modules are significantly distant from each other. [Figure 4] Table 3 shows the distance and proximity of certain drugs to certain disease and cognitive modules. The predicted gene expression modules targeted by drug combinations are significantly closer to the disease modules than randomly selected similar sized modules, supporting their application in the treatment of the corresponding symptoms. Prediction of gene expression networks for combinations of PDE4 inhibitors and β3 adrenergic agonists was not performed due to lack of data. In this table, negative Z scores represent statistically significant results, as assessed by permutation tests. [Diagram 5]A table summarizing the evidence for drug combinations is shown (Table 4). All combinations are shown for all or most of the conditions evaluated by the two methodologies. For the combination of PDE4 inhibitors + β3 adrenergic agonists, no gene expression data are available. Therefore, evaluation of this indication by perturbation network methods was not performed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] Without being bound to any particular theory, the inventors theorize that the solution to this problem is by combining a subemetic amount of a PDE4 inhibitor with a drug that has additive or synergistic effects on increasing cAMP signaling. In other words, the goal of this drug combination is to directly increase cAMP levels while preventing the induced degradation of cAMP by the PDE4 inhibitor, resulting in additive or greater effects. It has not been demonstrated that PDE4 inhibitors are effective antidepressants in humans, or that their combination with other drugs provides greater antidepressant effects than PDE4 alone. Therefore, there is considerable uncertainty as to whether drugs administered in combination with PDE4 can effectively treat depression. The combination of the present invention has several important advantages. First, the net increase in cells targeted by the two drugs is greater than when either drug is used alone at a low dose, resulting in fewer side effects, less severe side effects, or both. Secondly, the use of a subemetic amount of PDE4 inhibitor will ensure a higher tolerability of the combination, compared to the higher doses of PDE4 inhibitors that would otherwise be required to reach the same level of cAMP increase.Thirdly, a higher specificity may be achieved by combining a PDE4 inhibitor with an agent that affects neurons located in a subset of brain regions (or cell types) that are affected by the ubiquity of PDE4.This last advantage is important because it allows for a greater cAMP rise in a subset of cells, regions, or systems, thereby maximizing therapeutic efficacy while minimizing the potential for side effects.The inventors have surprisingly discovered at least three novel drug combinations that can enhance cAMP signaling for the treatment of depression or related conditions.

[0033] 5-HT 4 Combination of agonist and PDE4 inhibitor:One of the receptors whose activation increases cAMP levels is the serotonin 5-HT4 receptor. Activation of the 5-HT4 receptor by agonists (e.g., partial agonists) produces antidepressant-like effects in animals (17), suggesting an effect on the brain, but no 5-HT4 agonists have been developed for the treatment of neuropsychiatric conditions. However, the gastrointestinal and urinary tracts are prevalent with 5-HT4 receptors, and agonists of this receptor have been approved for indications such as irritable bowel syndrome and constipation. Experiments with human or porcine gut preparations have also found that the combination of PDE4 inhibitors and 5-HT4 agonists can result in synergistic or additive activation of neuromuscular neurons (18, 19). In addition, brain-penetrant oral 5-HT4 agonists have also been reported (20). While 5-HT4 agonists such as prucalopride are not used to treat depression (prucalopride is indicated for the treatment of constipation), we now disclose that the surprising combination of a 5-HT4 agonist and a subemetic amount of a PDE4 inhibitor can be used to treat symptoms associated with depression, anhedonia, motivation-related or cognitive disorders. For example, 0.25-4 mg of the 5-HT4 agonist prucalopride or a pharma- ceutically acceptable salt thereof (e.g., prucalopride succinate), or 1 μg-10 mg of the 5HT4 agonist capeserod (SL65.0155) or a pharma- ceutically acceptable salt thereof (e.g., capeserod hydrochloride) concomitantly with 100-500 mcg (e.g., 100-400 mcg, 100-300 mcg, 100-250 mcg, or 100-200 mcg) of the PDE4 inhibitor roflumilast or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast is one such combination. This combination may lead to a greater improvement in depression, anhedonia, motivational symptoms, or cognitive symptoms, and / or a reduction in side effects, compared to the use of a PDE4 inhibitor such as roflumilast alone.

[0034] H 3 Combination of antagonists or inverse agonists with PDE4 inhibitors:In addition to 5-HT4, histamine H3 receptor also binds to cAMP, but in this case, its activation inhibits cAMP production through binding to Gi protein. Therefore, drugs that are H3 antagonists or inverse agonists are expected to cause an increase in cAMP levels. Such various H3 antagonist or inverse agonist drugs have been tested for many cognitive disorders such as Alzheimer's disease, dementia, schizophrenia, multiple sclerosis, and attention deficit hyperactivity disorder, as well as changes in wakefulness such as narcolepsy and obstructive sleep apnea (21-23). ​​However, no such drugs are used to treat symptoms of depression. Furthermore, combination drugs that include H3 antagonists or inverse agonists have not been tested for the treatment of the above cognitive and wakefulness disorders. One embodiment of the present invention is the combination of H3 antagonists or inverse agonists with a subemetic amount of a PDE4 inhibitor for the treatment of symptoms related to depression, anhedonia, motivation-related or cognitive disorders. One example of an H3 antagonist or inverse agonist is pitolisant, which is approved for the treatment of narcolepsy. Thus, for example, 2-40 mg of pitolisant hydrochloride or an equivalent amount of pitolisant or different pharmacologic acceptable salts thereof, or 1-500 μg of iludavisant (CEP-26401) or a pharmacologic acceptable salt thereof (such as iludavisant hydrochloride) is used in combination with 100-500 mcg of the PDE4 inhibitor roflumilast or an equivalent amount of a pharmacologic acceptable salt of roflumilast, is one such combination. This combination may lead to a greater improvement in depression, anhedonia, motivational symptoms or cognitive symptoms, and / or a reduction in side effects, compared to the use of a PDE4 inhibitor such as roflumilast alone.

[0035] Nicotinic alpha 7 Combination of receptor agonists with PDE4 inhibitors:Without being bound by any particular theory, the inventors hypothesized that drugs that agonize the nicotinic α7 receptor may result in additive or synergistic increases in cAMP levels when used in combination with a PDE4 inhibitor. It has recently been reported that activation of the nicotinic α7 receptor in the hippocampus increases cAMP levels through a secondary effect on adenylyl cyclase, which produces cAMP (24). However, nicotinic α7 receptor agonists have not been used to treat depression, an example being varenicline, which has been approved for smoking cessation. Of note, varenicline has been approved as a smoking cessation treatment in humans, but initially suffered from a black box of increased risk of developing depression, seemingly the opposite of the inventors' goal. One embodiment of the present invention is a combination of a nicotinic α7 receptor agonist and a subemetic amount of a PDE4 inhibitor for the treatment of symptoms associated with depression, anhedonia, motivation-related or cognitive impairment. Thus, for example, 0.25-3 mg of varenicline or an equivalent amount of a pharma- ceutically acceptable salt of varenicline (such as varenicline tartrate) concomitant with 100-500 μg of the PDE4 inhibitor roflumilast or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast is one such combination, which may lead to greater improvement in depression, anhedonia, motivational symptoms or cognitive symptoms and / or reduced side effects compared to the use of a PDE4 inhibitor such as roflumilast alone.

[0036] β 3 Combination of an adrenergic agonist and a PDE4 inhibitor:The β3 adrenergic receptor is another G protein-coupled receptor present in the brain, whose activation increases cAMP signaling. Most β3 agonists are not brain penetrant and are therefore used for peripheral adrenergic stimulation, as in the case of mirabegron, which is approved for overactive bladder. Another β3 agonist, amibegron, is brain penetrant and showed promising antidepressant-like effects in animals (25), but failed to demonstrate efficacy in two acute treatment clinical trials (as required by the U.S. Food and Drug Administration to demonstrate efficacy), and its development for the treatment of depression in humans was discontinued (see https: / / www.sanofi.com / en / science-and-innovation / clinical-trials-and-results / our-disclosure-commitments / pharma / letter-a (accessed January 12, 2021)). Furthermore, combination drugs containing β3 agonists have not been tested for the treatment of depression. Therefore, it is unexpected to combine a PDE4 inhibitor with a failed promising antidepressant to be an effective treatment. One embodiment of the present invention is a combination of a β3 agonist with a subemetic amount of a PDE4 inhibitor for the treatment of symptoms related to depression, anhedonia, motivation-related or cognitive impairment. An example of a β3 agonist is amibegron. Thus, for example, 100-1400 mg of amibegron, or an equivalent amount of a pharma- ceutically acceptable salt thereof (e.g., amibegron hydrochloride), simultaneously with 100-500 mcg of the PDE4 inhibitor roflumilast or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast is one such combination. This combination may lead to a greater improvement in depression, anhedonia, motivation or cognitive symptoms and / or a reduction in side effects compared to the use of a PDE4 inhibitor such as roflumilast alone.

[0037] Combination of TAAR1 agonist and PDE4 inhibitor:Trace amine associated receptor 1 (TAAR1) is another G protein-coupled receptor present in the brain, whose activation increases cAMP signaling. Unlike the above receptors, this receptor is present intracellularly, not on the cell surface. To date, there are no drugs approved for indications that specifically target and activate TAAR1. One such TAAR1 agonist has shown initial promise in schizophrenia (26), but no TAAR1 agonist has been studied for efficacy in treating depression. Thus, the combination of a PDE4 inhibitor and a TAAR1 agonist is an unexpected combination to produce an effective antidepressant. One embodiment of the present invention is the combination of a TAAR1 agonist with a subemetic amount of a PDE4 inhibitor for the treatment of symptoms associated with depression, anhedonia, motivation-related or cognitive disorders. An example of a TAAR1 agonist is urotaront (SEP-363856). Another example is larmitaront (RO6889450). Thus, for example, 5-200 mg of urotalonto (SEP-363856), or an equivalent amount of a pharma- ceutically acceptable salt thereof, is administered simultaneously with 100-500 mcg of the PDE4 inhibitor roflumilast or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast, is one such combination. In another example, 5-300 mg of ralmitaronto (RO6889450), or an equivalent amount of a pharma- ceutically acceptable salt thereof, is administered simultaneously with 100-500 mcg of the PDE4 inhibitor roflumilast or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast, is one such combination. Both of these combinations may lead to a greater improvement in depression, anhedonia, motivational symptoms, or cognitive symptoms, and / or a reduction in side effects, compared to the use of a PDE4 inhibitor such as roflumilast alone.

[0038] Modeling drug combination effects based on gene expression:To understand the potential utility of the drug effects, the combinations described herein were evaluated for two properties: complementary exposure and combinatorial gene expression perturbation. These properties and the results of measuring these properties are described in the remainder of the text, but overall, these methods integrate mechanistic information about the drug (e.g., the effect of the drug on neuronal gene expression levels) and biological information about the indication (e.g., the difference in gene expression levels between individuals with a given disease and those without). Each combination and indication pair was evaluated separately for these two properties, and the results are presented here in parallel to support the utility of these drug effects.

[0039] Proximity to phenotypic networks and separation between single drugs: Cellular systems function as networks in which genes, their products, and other molecules interact to ensure proper cellular function. Targeting a gene or protein may affect the entire molecular network down to its downstream targets, affecting the entire pathway (29-30). Therefore, a systematic approach was used to analyze the entire gene network perturbed by drug combinations. In the context of biological networks, genes in pathways perturbed by effective drugs are more likely to be closer to genes involved in the disease and disease phenotype than off-label drugs (30). Furthermore, effective drug combinations should follow a complementary exposure pattern, where each single drug targets genes that affect a disease module (a module is composed of a subnetwork whose nodes are genes involved in the disease), but different drugs target separate disease topological neighborhoods, or sets of genes (31). For each combination, we assessed the proximity between the single drug module (when the module is composed of the drug target) and the depression, cognition, PTSD, schizophrenia, addiction, Parkinson's disease, and bipolar disorder modules, as well as their mutual separability. To this end, we constructed brain-specific protein-protein interaction (PPi) networks, where nodes represent genes expressed in the human brain and connections between nodes (called “edges”) represent experimentally determined physical interactions between gene products ( 31 – 33 ).

[0040] We identified reliable disease-associated genes based on mechanistic evidence from at least two published studies. All indications included genes that were differentially expressed in postmortem human brain. Additionally, for all indications except depression, genes from studies that were well supported by at least two pieces of evidence were included. One piece of evidence was genotype-based (e.g., gene-based results from genome-wide association studies), but at least one piece of evidence was also required to be functional evidence (e.g., expression quantitative trait loci, chromatin interaction studies, or gene expression studies in animal models). Finally, we filtered these gene lists to include only genes in the PPi network. The final sizes of the gene lists are as follows: 241 genes for depression (34-41), 470 genes for cognition (42-44), 26 genes for PTSD (45-55), 365 genes for schizophrenia (40, 56-64), 75 genes for addiction (55, 65-69), and 41 genes for Parkinson's disease (70-81).

[0041] To identify drug gene targets, direct target information was extracted from DGIdb (Drug-Gene Interaction Database (82)) and these direct target nodes were used as "bait" by expanding the module to include first neighbors (defined as genes directly connected to a node in the network). The resulting module was filtered to include only genes whose expression was affected by the drug of interest. These genes were assessed by gene expression data (83). Specifically, neural cell lines (neurons and neural precursors) were treated with various drugs and gene expression levels after treatment were measured. Genes whose expression levels were responsive to treatment were hypothesized to be affected (directly or indirectly) by the drug. Drugs for which gene expression data were available were selected with the same mechanism of drug action (MOA) as the combination. Specifically, gene expression data in response to rolipram was used to understand the effects of PDE4 inhibitors, e.g., roflumilast; for cisapride, to understand the effects of 5-HT4 agonists, e.g., prucalopride (both 5-HT4 agonists); for ciproxifan, to understand the effects of H3 inverse agonists, e.g., pitolisant or iludavisant; for amibegron, to understand the effects of β3 adrenergic agonists; and for tyramine, to understand the effects of TAAR1 agonists, e.g., SEP-363856 (urotaront) and ralmitaront (RO6889450). For β3 adrenergic agonists, there was no gene expression data available in the Subramanian et al. dataset, so only the direct targets of amibegron were used in the analysis. Analyzing drugs that are well representative of the mechanism of action of the drug of interest would therefore provide evidence of the utility of other drugs of the same class when used in combination.

[0042] To evaluate the proximity between the gene targeted by the drug of interest and the genes whose expression is perturbed in the disease, a permutation-based approach described in Guney et al. 2016 (84) and Cheng et al. 2019 (31) was used for indications other than psychiatric ones. Random modules that match the drug module in size and degree (measured by the amount of node connections, specifically the number of edges associated with the node) were selected 1000 times, and their distances to the disease module were calculated to generate a distribution of distances. The proximity of the drug module to the disease module is given by the Z-score of the relative distance to the distribution generated based on the random modules, approximated by (d_(drug-disease) - <d_(random-disease)> ) / (σ(d_(random-disease))), where <d_(random-disease)> is the mean of the distance distribution, and σ(d_(random-disease)) is the standard deviation. A Z-score <0 indicates that the drug module is significantly closer to the disease module than other gene sets within the network. Indeed, in these analyses, the Z-scores remained stable and were consistently negative or positive across multiple permutation shuffles, indicating the statistical significance of the results regarding the combination. Proximity was calculated using all disease and cognitive modules for each drug.

[0043] As shown in Table 1 (Figure 2), all drugs within the mechanism combinations are proximal to multiple disease modules, supporting their use in treating the corresponding symptoms. The exception is amibegron, for which gene expression data was not available. As a result of this data unavailability, initially the drug network was small and of poor completeness. To enhance the robustness of the brain-specific PPi network, nodes and edges extracted from the STRING database were added (32). As shown in Table 1, it was also found that the direct target module of amibegron is proximal to all disease and trait modules tested. By comparing the results of the combined drugs to other gene sets within networks with similar characteristics, it was demonstrated that this result is highly specific to the drugs selected.

[0044] To evaluate the separation between single drugs, we adopted the separation metric described in Cheng et al. 2019 (31), which compares the distance between nodes within each module with the distance between modules. As shown in Figure 1, a zero or positive separation value indicates that the two networks are topologically separated and therefore hit different neighborhoods in the disease network. Table 2 (Figure 3) shows that within each proposed combination, the single drugs are robustly separated, i.e., each drug in the combination targets the depression gene set but likely targets different genes in the set.

[0045] These results indicate that drug combinations follow a complementary exposure pattern characteristic of combinations with high efficacy and few side effects ( 31 ).

[0046] Predicting perturbation networks based on gene expression:In addition to complementary exposure analyses, we used publicly available gene expression data (83) to predict perturbation networks for each single drug and combination. Currently, there is no large-scale, readily available gene expression data for drug combinations. Therefore, we used a nonlinear approach that integrates single drug data to predict combinatorial gene expression changes, as described by Wu et al. 2010 (85), developed to identify combinations for type 2 diabetes. We first quantified gene expression changes in neurons after exposure to single drugs. Specifically, we used the dataset of neuronal drug administration from Subramanian et al. (83) to calculate the expression ratio of each gene between drug treatment for each single drug and the no-drug DMSO control. This information, a metric called the combined expression ratio, was used to predict, on a gene-by-gene basis, how gene expression levels would change if exposed to the two drugs simultaneously. To calculate this combined expression ratio, we used the single drug expression ratios calculated for each gene. If a gene was downregulated upon treatment with each single drug, the combined expression ratio was defined as the minimum of the single drug ratios. If a gene was upregulated in response to treatment with both drugs separately, the combined expression ratio was defined as the maximum of the single-drug ratios. If the ratios from each of the two drugs were in opposite directions, the combined expression ratio was calculated as the sum of the single-drug expression ratios (derived in Wu et al. 2010 (85)). The weight of each gene was then calculated by taking the absolute value of the logarithm of the calculated expression ratios. A gene was considered "perturbed" if its weight was 0.2 or greater, which corresponds to a 20% single-drug-mediated upregulation or downregulation of expression. For each single drug and combination, the perturbed genes were mapped onto the previously constructed brain-specific PPi network to evaluate the proximity of the combined module to the depression, cognition, PTSD, schizophrenia, addiction, and Parkinson's disease modules. As shown in Table 3 (Figure 4), the predicted combined networks were significantly close to multiple disease modules, supporting their application in the treatment of the corresponding symptoms.

[0047] Overview of Gene Expression Modeling: Table 4 (Figure 5) summarizes the findings from the two gene expression modeling methods for each combination. Taken together, the results demonstrate that these combinations show significant evidence of complementary exposures and combinatorial perturbation networks in close proximity to conditions where most, if not all, depression, anhedonia, motivation-related or cognition-related dysfunctions exist.

[0048] definition "PDE4 inhibitor" refers to a compound that blocks or inhibits the activity of phosphodiesterase 4 protein or any of its isoforms.Suitable PDE4 inhibitor antagonists include, but are not limited to, roflumilast, AVE8112, MEM1414, MEM1917, apremilast, cilomilast, crisaborole, ibudilast, luteolin, mesembrenone, piclamilast, rolipram, chlorvipram, GSK-256066, E-6005, MK-0873, BPN14770, HT-0712 and their pharmaceutically acceptable salts.

[0049] "5-HT4 agonist" refers to an agonist of the 5-HT4 receptor (including, but not limited to, 5-HT4 partial agonists), including, but not limited to, prucalopride, cisapride, BIMU-8, CJ-033466, ML-10302, mosapride, renzapride, RS-67506, RS67333, SL65.0155 (capeserod), tegaserod, zacopride, metoclopramide, sapride and pharma- ceutically acceptable salts thereof (e.g., prucalopride succinate or capeserod hydrochloride).

[0050] "H3 antagonist" or "H3 inverse agonist" refers to a compound that blocks activity at the H3 receptor. Suitable H3 antagonists or inverse agonists include, but are not limited to, pitolisant, ABT-28, BF2.649, CEP-26401 (ildavisan), GSK-189254, GSK-239512, MK-0249, PF-3654746 and its pharmaceutically acceptable salts (e.g., pitolisant hydrochloride or ildavisan hydrochloride).

[0051] "Nicotinic α7 receptor agonist" or "alpha7 receptor agonist" refers to an agonist (including, but not limited to, a partial agonist) of a nicotinic receptor that contains the α7 subunit. Suitable α7 nicotinic receptor agonists include, but are not limited to, varenicline, tilorone, A-582941, AR-R17779, TC-1698, bradanicline, ensenicline, GTS-21, PHA-543613, PNU-292987, PHA-709829, SSR-180711, tropisetron, WAY-317538, anabasine, epiboxidine, PNU-120596, NS-1738, AVL-3288, A867744, ivermectin, BNC210, or a pharma- ceutically acceptable salt thereof (e.g., varenicline tartrate).

[0052] "β3 adrenergic agonist" or "β3 agonist" refers to an agonist of the β3 adrenergic receptor. Suitable β3 agonists include amibegron, mirabegron, vibegron, ritobegron, BRL37344, solabegron, or a pharmaceutically acceptable salt thereof.

[0053] "TAAR1 agonist" refers to an agonist of the trace amine associated receptor 1. Suitable TAAR1 agonists include urotaront (SEP-363856), larmitaront (RO6889450), RO5166017, RO5256390, RO5203648, RO5263397, tyramine, amphetamine, methamphetamine, and 3,4-methylenedioxy-methamphetamine (MDMA) or a pharmaceutically acceptable salt thereof.

[0054] Unless otherwise stated, the term "about" in connection with a numerical value or range refers to ±10% of the stated numerical value or range.

[0055] As used herein, "effective" in an amount effective to achieve a purpose means an amount of a component sufficient to produce an indicated therapeutic response without undue adverse side effects (e.g., toxicity, irritation, or allergic reaction) commensurate with a reasonable benefit / risk ratio when used in the methods disclosed herein. The specific effective amount will vary depending on factors such as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of treatment, the nature of concurrent therapy (if any), and the particular formulation used, as well as the structure of the compound or its derivatives.

[0056] As used herein, "treat" or "treating" includes, for example, inducing inhibition, regression, or cessation of a disorder and / or disease, such as depression, or alleviating, alleviating, suppressing, inhibiting, reducing the severity of the disease or disorder, or eliminating or substantially eliminating or ameliorating symptoms.

[0057] As used herein, the terms "subject" and "patient" are used interchangeably and refer to a human patient, unless otherwise indicated.

[0058] The diagnoses of various mental and psychological disorders, including depression, are defined, for example, in the Diagnostic and Statistical Manual of Mental Disorders (5 th Ed. DSM-5, American Psychiatric Association, 2013).

[0059] Treatment Method Each active ingredient (e.g., PDE4 inhibitor, 5-HT4 agonist, H3 antagonist or inverse agonist, nicotinic α7 receptor agonist, β3 adrenergic agonist or TAAR1 agonist) may be administered by any route, for example, orally, nasally, transdermally, rectally, transdermally, or by parenteral injection. The preferred route of administration is oral. The active ingredient may be administered in the form of a tablet, capsule, granule, or oral liquid.

[0060] The methods and pharmaceutical compositions described herein may be used to treat (a) depression (e.g., major depressive disorder or bipolar I disorder), (b) psychiatric or neurological disorders in which depression, anhedonia, motivation-related or cognitive dysfunction is present, or (c) one or more symptoms associated with depression, anhedonia, or motivation-related disorder. Types of depression that may be treated include, but are not limited to, major depressive disorder, treatment-resistant depression, residual depressive symptoms, and dysthymia. Psychiatric or neurological disorders in which depressive states, anhedonia, motivation-related or cognitive dysfunction are present that may be treated include, but are not limited to, depression as part of bipolar I disorder or bipolar II disorder, addiction (e.g., drug addiction), post-traumatic stress disorder, schizophrenia (particularly associated negative or cognitive symptoms), or Parkinson's disease (non-motor features such as depression, apathy, or cognitive impairment). In one embodiment, the method treats one or more non-motor features of Parkinson's disease. Depression-related symptoms that can be treated include, but are not limited to, depressed mood, blunted affect, anhedonia, alexithymia, and apathy.Motivation-related disorders that can be treated include, but are not limited to, the inability to participate in previously rewarding experiences, reduced social interest or motivation, inattention to social input, reduced psychomotor activity, excessive sleep, avoidance of activities and social interactions, and reduced appetite.Cognitive disorders include, but are not limited to, the inability to focus on tasks that require attention, reduced executive function, difficulty inhibiting inappropriate responses, and memory formation or recall defects.

[0061] Generally, the amount of active ingredient administered is sufficient to increase the cAMP molecule signaling in the brain.In one embodiment, the amount of each ingredient administered daily can be as shown in the table below. [Table 1-1] [Table 1-2] [Table 1-3]

[0062] In one embodiment, administer the PDE4 inhibitor in an amount that is less than emetic.In a preferred embodiment, administer the PDE4 inhibitor in an amount that generally does not cause nausea or vomiting in subject.In another embodiment, administer the PDE4 inhibitor in an amount that does not cause emesis in subject.

[0063] In accordance with the practice of the invention, each active ingredient may be administered one or more times daily, daily, weekly, monthly, or yearly.

[0064] Pharmaceutical Compositions The pharmaceutical composition may contain a sub-emetic amount of the PDE4 inhibitor. In a preferred embodiment, the composition contains an amount of the PDE4 inhibitor that, when administered (e.g., orally), generally does not cause nausea or vomiting in the subject. In another embodiment, the composition contains an amount of the PDE4 inhibitor that, when administered (e.g., orally), does not cause vomiting in the subject. In yet another embodiment, the pharmaceutical composition contains the amount of the PDE4 inhibitor and other active ingredients listed in the table provided above per day. In yet another embodiment, the pharmaceutical composition contains the amount of the PDE4 inhibitor and other active ingredients that is equal to the total amount listed in the table above per day when administered twice a day.

[0065] In addition to the active ingredient, the pharmaceutical composition may contain one or more pharma- ceutical acceptable excipients.The pharmaceutical composition may be suitable for any route of administration, such as nasal, rectal, intercisternal, oral, intramuscular, intrasternal, intradermal, intrasynovial, intravenous, intraperitoneal, intraocular, periosteal, intraarticular injection, infusion, oral, topical, inhalation, parenteral, subcutaneous, implantable pump, continuous infusion, gene therapy, intranasal, intrathecal, intraventricular, transdermal, or by spray, patch or injection.

[0066] The pharmaceutical compositions may be formulated as solid dosage forms such as capsules, pills, softgels, tablets, caplets, troches, wafers, sprinkles, or chewables for oral administration.The pharmaceutical compositions may be formulated as liquid dosage forms such as elixirs, suspensions, or syrups.

[0067] The pharmaceutical compositions may also be provided in a dosage form for transdermal application (eg, a patch or ointment) or for oral administration.

[0068] The pharmaceutical composition may be in liquid form or suspension to be applied to the nasal or oral cavity using a dropper, sprayer or container.The pharmaceutical composition may be in solid, salt, or powder form to be applied to the nasal or oral cavity using a sprayer, forced air or container.

[0069] The pharma- ceutically acceptable excipient may be selected from pharma- ceutically acceptable carriers, binders, diluents, adjuvants, or vehicles, such as preservatives, fillers, polymers, disintegrants, glidants, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, perfumes, lubricants (e.g., magnesium stearate), acidifiers, colorants, dyes, preservatives, and dispersing agents. Such pharma- ceutically acceptable excipients are described in Handbook of Pharmaceutical Excipients, 6 th Ed., Pharmaceutical Press and American Pharmaceutical Association (2009).

[0070] Pharmaceutically acceptable carriers are generally non-toxic to recipients at the dosages and concentrations used, and are compatible with other ingredients of the formulation. Examples of pharma-ceutically acceptable carriers include water, saline, dextrose solution, ethanol, polyols, vegetable oils, fats, ethyl oleate, liposomes, wax polymers, for example, gel-forming polymers and non-gel-forming polymers, and suitable mixtures thereof. Carriers may also contain minor amounts of additives, such as substances that enhance isotonicity and chemical stability. Such materials are non-toxic to recipients at the dosages and concentrations used and include buffers, such as phosphate, citrate, succinate, acetic acid and other organic acids or their salts; antioxidants such as ascorbic acid; low molecular weight (less than about 10 residues) polypeptides, such as polyarginine or tripeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids, such as glycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates, including cellulose or derivatives thereof, glucose, mannose, or dextrin; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or non-ionic surfactants, such as polysorbates, poloxamers, or PEG.

[0071] Examples of binders include, but are not limited to, microcrystalline cellulose and cellulose derivatives, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, molasses, polyvinylpyrrolidone, povidone, crospovidones, sucrose and starch paste.

[0072] Examples of diluents include, but are not limited to, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.

[0073] Examples of excipients include, but are not limited to, starch, surfactants, lipophilic vehicles, hydrophobic vehicles, pregelatinized starch, microcrystalline cellulose, lactose, milk sugar, sodium citrate, calcium carbonate, and dicalcium phosphate.Typical excipients for dosage forms such as softgels include gelatin for capsules, and oils such as soybean oil, rice bran oil, canola oil, olive oil, corn oil, and other similar oils; glycerol, liquid polyethylene glycol, and vitamin E TPGS as surfactants.

[0074] Examples of disintegrants include, but are not limited to, complex silicates, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose.

[0075] Examples of glidants include, but are not limited to, colloidal silicon dioxide, talc, and cornstarch.

[0076] Examples of wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.

[0077] Examples of lubricants include magnesium or calcium stearate, sodium lauryl sulfate, talc, starch, lycopodium and stearic acid, and high molecular weight polyethylene glycols.

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[0079] All references cited herein are hereby incorporated by reference.

Claims

1. PDE4 inhibitors and 5-HT ４ Agonist, H ３ antagonist or inverse agonist, or nicotinic alpha ７ Receptor agonist, beta ３ and at least one of an adrenergic agent or a TAAR1 agonist.

2. The composition comprises: (a) a PDE4 inhibitor; and (b) a 5-HT ４ The pharmaceutical composition of claim 1 comprising an agonist.

3. 3. The pharmaceutical composition of claim 2, comprising: (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof; and (b) prucalopride, or a pharma- ceutically acceptable salt thereof.

4. 4. The pharmaceutical composition of claim 3, wherein the composition comprises: (a) about 100 to about 500 mcg of roflumilast or an equivalent pharma- ceutically acceptable salt of roflumilast; and (b) about 0.25 to about 4 mg of prucalopride or an equivalent pharma- ceutically acceptable salt of prucalopride.

5. 3. The pharmaceutical composition of claim 2, comprising: (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof; and (b) prucalopride, or a pharma- ceutically acceptable salt thereof.

6. 4. The pharmaceutical composition of claim 3, wherein the composition comprises: (a) about 100 to about 500 mcg of roflumilast or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast; and (b) about 1 μg to about 10 mg of capeserod or an equivalent amount of a pharma- ceutically acceptable salt of capeserod.

7. The composition comprises: (a) a PDE4 inhibitor; and (b) H ３ The pharmaceutical composition of claim 1 comprising an antagonist or an inverse agonist.

8. 8. The pharmaceutical composition of claim 7, wherein the composition comprises: (a) roflumilast, an N-oxide thereof, or a pharma- ceutically acceptable salt thereof; and (b) pitolisant or a pharma- ceutically acceptable salt thereof.

9. 9. The pharmaceutical composition of claim 8, wherein the composition comprises: (a) about 100 to about 500 mcg of roflumilast or an equivalent pharma- ceutically acceptable salt of roflumilast; and (b) about 2 to about 40 mg of pitolisant or a pharma- ceutically acceptable salt thereof equivalent to pitolisant hydrochloride.

10. 8. The pharmaceutical composition of claim 7, wherein the composition comprises: (a) roflumilast, an N-oxide thereof, or a pharma- ceutically acceptable salt thereof; and (b) irudabisanto, or a pharma- ceutically acceptable salt thereof.

11. 11. The pharmaceutical composition of claim 10, wherein the composition comprises: (a) about 100 to about 500 mcg of roflumilast or an equivalent pharma- ceutically acceptable salt of roflumilast; and (b) about 1 to about 500 μg of irudabisanto or a pharma- ceutically acceptable salt thereof equivalent to irudabisanto hydrochloride.

12. The composition comprises: (a) a PDE4 inhibitor; and (b) a nicotinic alpha ７ The pharmaceutical composition of claim 1 comprising a receptor agonist.

13. 13. The pharmaceutical composition of claim 12, comprising: (a) roflumilast, an N-oxide thereof, or a pharma- ceutically acceptable salt thereof; and (b) varenicline or a pharma- ceutically acceptable salt thereof.

14. 14. The pharmaceutical composition of claim 13, wherein the composition comprises: (a) about 100 to about 500 mcg of roflumilast or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast; and (b) about 0.25 to about 3 mg of varenicline or an equivalent amount of a pharma- ceutically acceptable salt of varenicline.

15. The composition comprises: (a) a PDE4 inhibitor; and (b) a β ３ 10. The pharmaceutical composition of claim 1 comprising an adrenergic agent.

16. 16. The pharmaceutical composition of claim 15, comprising: (a) roflumilast, an N-oxide thereof, or a pharma- ceutically acceptable salt thereof; and (b) amibegron or a pharma- ceutically acceptable salt thereof.

17. 17. The pharmaceutical composition of claim 16, wherein the composition comprises: (a) about 100 to about 500 mcg of roflumilast or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast; and (b) about 100 to about 1400 mg of amibegron or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast.

18. 2. The pharmaceutical composition of claim 1, wherein the composition comprises (a) a PDE4 inhibitor and (b) a TAAR-1 agonist.

19. 19. The pharmaceutical composition of claim 18, comprising: (a) roflumilast, an N-oxide thereof, or a pharma- ceutically acceptable salt thereof; and (b) urotalont, or a pharma- ceutically acceptable salt thereof.

20. 20. The pharmaceutical composition of claim 19, wherein the composition comprises: (a) about 100 to about 500 mcg of roflumilast or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast; and (b) about 5 to about 200 mg of urotalonto or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast.

21. 19. The pharmaceutical composition of claim 18, comprising: (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof; and (b) larmitront, or a pharma- ceutically acceptable salt thereof.

22. 22. The pharmaceutical composition of claim 21, wherein the composition comprises: (a) about 100 to about 500 mcg of roflumilast or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast; and (b) about 5 to about 300 mg of ralmitaront or an equivalent amount of a pharma- ceutically acceptable salt of roflumilast.

23. 13. The pharmaceutical composition of any one of the preceding claims, comprising a sub-emetic amount of component (a) and effective amounts of components (a) and (b) together to treat an intended disorder, such as (a) depression (e.g. major depressive disorder or bipolar I disorder), (b) a psychiatric or neurological disorder in which anhedonia, motivation-related or cognitive-related dysfunction is present, or (c) one or more symptoms associated with depression, anhedonia, or motivation-related or cognitive-related dysfunction.

24. (a) a psychiatric or neurological disorder in which anhedonia, motivation-related or cognitive-related dysfunction is present, or (c) one or more symptoms associated with depression, anhedonia, or motivation-related or cognitive-related dysfunction, in a subject in need thereof. ４ Agonist, H ３ antagonist or inverse agonist, nicotinic alpha ７ Receptor agonist, beta ３ Use of at least one of an adrenergic agent or a TAAR1 agonist.

25. The pharmaceutical composition comprises an effective amount of (a) a PDE4 inhibitor and (b) a 5-HT ４ 25. The use according to claim 24, comprising an agonist.

26. The use according to claim 25, wherein the medicament comprises effective amounts of (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof, and (b) prucalopride or a pharma- ceutically acceptable salt thereof.

27. 1. A pharmaceutical composition comprising roflumilast or a pharma- ceutical acceptable salt of roflumilast, and prucalopride or a pharma- ceutical acceptable salt of prucalopride, characterized in that: (a) about 100 to about 500 mcg of roflumilast or an equivalent amount of a pharma- ceutical acceptable salt of roflumilast per day; and (b) about 0.25 to about 4 mg of prucalopride or an equivalent amount of a pharma- ceutical acceptable salt of prucalopride per day.

28. The use of claim 25, wherein the medicament comprises effective amounts of (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof, and (b) capeserod or a pharma- ceutically acceptable salt thereof.

29. A pharmaceutical composition comprising roflumilast or a pharma- ceutical acceptable salt of roflumilast, and capeserodof or a pharma- ceutical acceptable salt of capeserodof, characterized in that (a) about 100 to about 500 mcg of roflumilast or an equivalent amount of a pharma- ceutical acceptable salt of roflumilast per day, and (b) about 1 μg to about 10 mg of capeserodof or an equivalent amount of a pharma- ceutical acceptable salt of capeserodof per day.

30. The pharmaceutical composition comprises an effective amount of (a) a PDE4 inhibitor and (b) H ３ 25. The use according to claim 24, comprising an agonist or an inverse agonist.

31. The use of claim 30, wherein the medicament comprises effective amounts of (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof, and (b) pitolisant or a pharma- ceutically acceptable salt thereof.

32. A pharmaceutical composition comprising roflumilast or a pharma- ceutically acceptable salt of roflumilast, and pitolisant or a pharma- ceutically acceptable salt of pitolisant, characterized in that (a) about 100 to about 500 mcg of roflumilast or an equivalent pharma- ceutically acceptable salt of roflumilast per day, and (b) an amount of pitolisant or an equivalent pharma- ceutically acceptable salt of pitolisant equivalent to about 2 to about 40 mg of pitolisant hydrochloride per day.

33. The use of claim 30, wherein the medicament comprises effective amounts of (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof, and (b) iludabisan or a pharma- ceutically acceptable salt thereof.

34. A pharmaceutical composition comprising roflumilast or a pharma- ceutically acceptable salt of roflumilast, and irudabisan or a pharma- ceutically acceptable salt thereof, characterized in that the composition is used to administer (a) about 100 to about 500 mcg of roflumilast or an equivalent pharma- ceutically acceptable salt of roflumilast per day, and (b) an amount of irudabisan or a pharma- ceutically acceptable salt thereof equivalent to about 1 to about 500 μg of irudabisan hydrochloride per day.

35. The pharmaceutical composition comprises an effective amount of (a) a PDE4 inhibitor and (b) a nicotinic alpha ７ 25. The use according to claim 24, comprising a receptor agonist.

36. The use of claim 35, wherein the medicament comprises effective amounts of (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof, and (b) varenicline or a pharma- ceutically acceptable salt thereof.

37. 1. A pharmaceutical composition comprising roflumilast or a pharma- ceutical acceptable salt of roflumilast, and varenicline or a pharma- ceutical acceptable salt of varenicline, characterized in that: (a) about 100 to about 500 mcg of roflumilast or an equivalent amount of a pharma- ceutical acceptable salt of roflumilast per day; and (b) about 0.25 to about 3 mg of varenicline or an equivalent amount of a pharma- ceutical acceptable salt of varenicline per day.

38. The pharmaceutical composition comprises an effective amount of (a) a PDE4 inhibitor and (b) a β ３ 25. The use according to claim 24, comprising an adrenergic agonist.

39. The use according to claim 38, wherein the medicament comprises effective amounts of (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof, and (b) amibegron or a pharma- ceutically acceptable salt thereof.

40. 1. A pharmaceutical composition comprising roflumilast or a pharma- ceutical acceptable salt of roflumilast, and amibegron or a pharma- ceutical acceptable salt thereof, characterized in that the composition is used so that (a) about 100 to about 500 mcg of roflumilast or an equivalent amount of a pharma- ceutical acceptable salt of roflumilast is administered per day, and (b) about 100 to about 1,400 mg of amibegron or an equivalent amount of a pharma- ceutical acceptable salt thereof is administered per day.

41. The use of claim 24, wherein the medicament comprises effective amounts of (a) a PDE4 inhibitor and (b) a TAAR-1 agonist.

42. The use of claim 41, wherein the medicament comprises effective amounts of (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof, and (b) urotalont or a pharma- ceutically acceptable salt thereof.

43. A pharmaceutical composition comprising roflumilast or a pharma- ceutical acceptable salt of roflumilast, and urotaront or a pharma- ceutical acceptable salt thereof, characterized in that (a) about 100 to about 500 mcg of roflumilast or an equivalent amount of a pharma- ceutical acceptable salt of roflumilast per day, and (b) about 5 to about 200 mg of urotaront or an equivalent amount of a pharma- ceutical acceptable salt thereof per day are administered.

44. The use of claim 41, wherein the medicament comprises effective amounts of (a) roflumilast, its N-oxide, or a pharma- ceutically acceptable salt thereof, and (b) larmitront or a pharma- ceutically acceptable salt thereof.

45. A pharmaceutical composition comprising roflumilast or a pharma- ceutical acceptable salt of roflumilast, and larmitront or a pharma- ceutical acceptable salt thereof, characterized in that (a) about 100 to about 500 mcg of roflumilast or an equivalent amount of a pharma- ceutical acceptable salt of roflumilast is administered per day, and (b) about 5 to about 300 mg of larmitront or an equivalent amount of a pharma- ceutical acceptable salt thereof is administered per day.

46. 46. ​​The pharmaceutical composition of any one of claims 27, 29, 32, 34, 37, 40, 43, and 45, comprising administering a sub-emetic amount of component (a) and effective amounts of components (a) and (b) together to treat one or more symptoms associated with (a) depression (e.g., major depressive disorder or bipolar I disorder), (b) a psychiatric or neurological disorder in which anhedonia, motivation-related or cognitive-related dysfunction is present, or (c) depression, anhedonia, or motivation-related or cognitive-related dysfunction.

47. 47. The pharmaceutical composition of claim 46, wherein the psychiatric or neurological disorder is post-traumatic stress disorder, schizophrenia, addiction, or Parkinson's disease.

48. 47. The pharmaceutical composition of claim 46, wherein the psychiatric or neurological disorder is one or more non-motor features of Parkinson's disease.

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