US 20150231126A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0231126A1 Peters et al. (43) Pub. Date: Aug. 20, 2015

(54) COMBINATIONS OF 5-HT2A INVERSE Publication Classification AGONSTS AND ANTAGONSTS WITH ANTIPSYCHOTICS (51) Int. Cl. A613 L/4468 (2006.01) A 6LX3/59 (2006.01) (71) Applicant: ACADIA Pharmaceuticals Inc., San A613 L/496 (2006.01) Diego, CA (US) A613 L/554 (2006.01) G06F 9/00 (2006.01) (72) Inventors: Perry Peters, San Diego, CA (US); A6II 45/06 (2006.01) David Furlano, San Diego, CA (US); A633/00 (2006.01) Daun Bahr, San Diego, CA (US); A613 L/454 (2006.01) Daniel Van Kammen, San Diego, CA A614.9/00 (2006.01) (US); Mark Brann, Rye, NH (US) A613 L/45 (2006.01) A613 L/435 (2006.01) (52) U.S. Cl. (21) Appl. No.: 14/702,313 CPC ...... A6 IK3I/4468 (2013.01); A61 K3I/451 (2013.01); A61 K3I/519 (2013.01); A61 K 31/496 (2013.01); A61 K3I/554 (2013.01); (22) Filed: May 1, 2015 A61K 31/435 (2013.01); A61K 45/06 (2013.01); A61 K33/00 (2013.01); A61 K 3 1/454 (2013.01); A61K 49/0008 (2013.01): Related U.S. Application Data G06F 19/706 (2013.01) (60) Continuation of application No. 13/754,769, filed on (57) ABSTRACT Jan. 30, 2013, now Pat. No. 9,050,343, which is a Combinations of 5-HT2A inverse agonists or antagonists division of application No. 12/051,807, filed on Mar. Such as with antipsychotics Such as 19, 2008, now abandoned. are shown induce a rapid onset of antipsychotic action and increase the responders when compared to therapy with the (60) Provisional application No. 60/895,735, filed on Mar. antipsychotic alone. These effects can be achieved at a low 19, 2007, provisional application No. 60/908,921, dose of the antipsychotic, thereby reducing the incidence of filed on Mar. 29, 2007, provisional application No. side effects. The combinations are also effective at decreases 61/012,771, filed on Dec. 10, 2007, provisional appli the incidence of weight gain and increased glucose or prolac cation No. 61/026,092, filed on Feb. 4, 2008. tin levels caused by the antipsychotic. Patent Application Publication Aug. 20, 2015 Sheet 1 of 42 US 2015/0231126 A1

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COMBINATIONS OF 5-HT2A INVERSE eration, or inhibition of second messenger molecules Such as AGONSTS AND ANTAGONSTS WITH cyclic AMP. inositol phosphates, and diacylglycerol. These ANTIPSYCHOTICS second messengers then modulate the function of a variety of intracellular enzymes, including kinases and ion channels, RELATED APPLICATIONS which ultimately affect cellular excitability and function. 0007. At least 15 genetically distinct 5-HT receptor sub 0001. This application claims the benefit of U.S. Provi types have been identified and assigned to one of seven fami sional Application Nos. 60/895,735, filed Mar. 19, 2007: lies (5-HT1-7). Each subtype displays a unique distribution, 60/908,921, filed Mar. 29, 2007: 61/012,771, filed Dec. 10, preference for various ligands, and functional correlate(s). 2007; and 61/026,092, filed Feb. 4, 2008, all of which are 0008 may be an important component in vari entitled “COMBINATIONS OF N-(1-METHYLPIPERI ous types of pathological conditions such as certain psychi DIN-4-YL)-N-(4-FLUOROPHENYLMETHYL)-N'-(4-(2- atric disorders (depression, aggressiveness, panic attacks, METHYLPROPYLOXY)PHENYLMETHYL) WITH obsessive compulsive disorders, psychosis, Schizophrenia, ANTIPSYCHOTICS” and are incorporated herein by refer Suicidal tendency), certain neurodegenerative disorders ence in their entirety. (Alzheimer-type dementia, Parkinsonism, Huntington's cho BACKGROUND OF THE INVENTION rea), anorexia, bulimia, disorders associated with alcoholism, cerebral vascular accidents, and (Mehzer, Neurop 0002 1. Field of the Invention sychopharmacology, 21:106S-115S (1999); Barnes & Sharp, 0003. The present invention relates to the fields of chem Neuropharmacology, 38: 1083-1152 (1999); Glennon, Neu istry and medicine. More particularly, Some embodiments of rosci. Biobehavioral Rev., 14:35 (1990)). the invention relate to co-administration of 5-HT2A receptor 0009 Given the broad distribution of serotonin within the inverse agonists or antagonists with antipsychotics. body and its role in a wide range of physiological and patho 0004 2. Description of the Related Art logical processes, it is understandable that there is tremen 0005 Serotonin or 5-hydroxytryptamine (5-HT) plays a dous interest in that affect systems (Ger significant role in the functioning of the mammalian body. In son, et al., The Peripheral Actions of 5-Hydroxytryptamine, the central nervous system, 5-HT is an important neurotrans 246 (1989), Saxena, et al., J. Cardiovascular Pharmacol. 15: mitter and neuromodulator that is implicated in Such diverse Supp. 7 (1990)). behaviors and responses as sleeping, eating, locomotion, per 0010. The effects of serotonin are mediated by at least 15 ceiving pain, learning and memory, sexual behavior, control genetically distinct 5-HT receptor subtypes have been iden ling body temperature and blood pressure. In the spinal col tified and assigned to one of seven families (5-HT1-7). Each umn, serotonin plays an important role in the control systems Subtype displays a unique distribution, preference for various of the afferent peripheral nociceptors (Moulignier, Rev. Neu ligands, and functional correlate(s). Serotonin receptors are rol. 150:3-15, (1994)). Peripheral functions in the cardiovas members of a large human gene family of membrane-Span cular, hematological and gastrointestinal systems have also ning proteins that function as transducers of intercellular been ascribed to 5-HT. 5-HT has been found to mediate a communication. They exist on the Surface of various cell variety of contractile, secretory, and electrophysiologic types, including neurons and platelets, where, upon their effects including vascular and nonvascular Smooth muscle activation by either their endogenous ligand serotonin or contraction, and platelet aggregation. (Fuller, Biology of exogenously administered drugs, they change their confor Serotonergic Transmission, 1982, Boullin, Serotonin In Men mational structure and Subsequently interact with down tal Abnormalities 1:316 (1978); Barchas, et al., Serotonin and stream mediators of cellular signaling. Many of these recep Behavior, (1973)). The 5-HT2A receptor subtype (also tors, including the 5-HT2A subclass, are G-protein coupled referred to as subclass) is widely yet discretely expressed in receptors (GPCRs) that signal by activating guanine nucle the human brain, including many cortical, limbic, and fore otide binding proteins (G-proteins), resulting in the genera brain regions postulated to be involved in the modulation of tion, or inhibition of second messenger molecules Such as higher cognitive and affective functions. This receptor Sub cyclic AMP. inositol phosphates, and diacylglycerol. These type is also expressed on mature platelets where it mediates, second messengers then modulate the function of a variety of in part, platelet aggregation, one of the initial steps in the intracellular enzymes, including kinases and ion channels, process of vascular thrombosis. which ultimately affect cellular excitability and function. 0006 Given the broad distribution of serotonin within the 0011. The 5-HT2A receptor subtype (also referred to as body, it is understandable that tremendous interest in drugs Subclass) is widely yet discretely expressed in the human that affect serotonergic systems exists (Gershon, et al., The brain, including many cortical, limbic, and forebrain regions Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); Sax postulated to be involved in the modulation of higher cogni ena, et al. J. Cardiovascular Pharmacol 15. Supp. 7 (1990)). tive and affective functions. This receptor subtype is also Serotonin receptors are members of a large human gene fam expressed on mature platelets where it mediates, in part, ily of membrane-spanning proteins that function as transduc platelet aggregation, one of the initial steps in the process of ers of intercellular communication. They exist on the Surface vascular thrombosis. Recent evidence strongly implicates the of various cell types, including neurons and platelets, where, 5-HT2 receptor subtype in the etiology of such medical con upon their activation by either their endogenous ligand sero ditions as hypertension, thrombosis, migraine, vasospasm, tonin or exogenously administered drugs, they change their ischemia, depression, anxiety, psychosis, Schizophrenia, conformational structure and Subsequently interact with sleep disorders and appetite disorders. downstream mediators of cellular signaling. Many of these 0012 Schizophrenia is a particularly devastating neurop receptors, including the 5-HT2A subclass, are G-protein sychiatric disorder that affects approximately 1% of the coupled receptors (GPCRs) that signal by activating guanine human population. It has been estimated that the total finan nucleotide binding proteins (G-proteins), resulting in the gen cial cost for the diagnosis, treatment, and lost Societal pro US 2015/0231126 A1 Aug. 20, 2015

ductivity of individuals affected by this disease exceeds 2% of activity at a receptor. In that they alone can activate or inac the gross national product (GNP) of the United States. Cur tivate these molecules, respectively. In contrast, classic or rent treatment primarily involves pharmacotherapy with a neutral antagonists compete againstagonists and inverseago class of drugs known as antipsychotics. Antipsychotics are nists for access to the receptor, but do not possess the intrinsic effective in ameliorating positive symptoms (e.g., hallucina ability to inhibit elevated basal or constitutive receptor tions and delusions), yet they frequently do not improve nega responses. tive symptoms (e.g., social and emotional withdrawal, apathy, and poverty of speech). SUMMARY OF THE INVENTION 0013 Currently, nine major classes of antipsychotics are 0017. Some embodiments described herein include a prescribed to treat psychotic symptoms. Use of these com method of treating a condition amenable to treatment with an pounds is limited, however, by their side effect profiles. antipsychotic, comprising administering a first amount of a Nearly all of the “typical' or older generation compounds 5-HT2A inverse agonist or antagonist and administering a have significant adverse effects on human motor function. second amount of an antipsychotic agent, wherein the first These “extrapyramidal' side effects, so termed due to their and second amounts are such that an efficacious effect is effects on modulatory human motor systems, can be both achieved faster than when the antipsychotic agent is admin acute (e.g., dystonia reactions, a potentially life threatening istered alone at an efficacious dose. In some embodiments, but rare neuroleptic malignant syndrome) and chronic (e.g., the second amount is less than a maximal dose of the antip akathisias, tremors, and tardive dyskinesia). develop sychotic agent when it is administered alone. In some ment efforts have, therefore, focused on newer "atypical embodiments, the second amount is less than an efficacious agents free of some of these adverse effects. However, atypi dose of the antipsychotic agent when it is administered alone. cal agents also have the potential for serious side effects 0018. In some embodiments, the first and second amounts including increased risk of stroke, abnormal shifts in sleep are such that the severity or onset of one or more side effects patterns, extreme tiredness and weakness, metabolic disor due to the antipsychotic agent are reduced as compared to ders (including hyperglycemia and diabetes), and weight administration of an efficacious dose of the antipsychotic gain. One of the most common reasons for noncompliance agent alone. In some embodiments, the side effect is weight and discontinued use of antipsychotic is weight gain. In some embodiments, the side effect is selected from gain. Non-compliance can lead to increased hospitalization the group consisting of an extrapyramidal side effect, a his and health care costs. taminic side effect, an alpha adrenergic side effect, and an 0014 Antipsychotic drugs have been shown to interact anticholinergic side effect. In some embodiments, the side with a large number of central neurotrans effect is selected from the group consisting of stroke, tremors, mitter receptors, including dopaminergic, serotonergic, adr sedation, gastrointestinal problems, neurological problems, energic, muscarinic, and histaminergic receptors. It is likely increased risk of death, cerebrovascular events, movement that the therapeutic and adverse effects of these drugs are disorder, dystonia, akathisia, parkinsoniam movement disor mediated by distinct receptor subtypes. The high degree of der, tardive dyskinesia, cognitive disorders, prolactinemia, genetic and pharmacological homology between these recep catalepsy, psychosis, neuroleptic malignant syndrome, heart tor Subtypes has hampered the development of Subtype-se problems, pulmonary problems, diabetes, liver failure, Sui lective compounds, as well as the determination of the normal cidality, sedation, orthostatic hypotension, choking, dizzi physiologic or pathophysiologic role of any particular recep ness, tachycardia, blood abnormalities, abnormal triglyceride tor subtype. Thus there is a need to develop drugs that are levels, increased cholesterol levels, dyslipidemia, hypergly selective for individual receptor classes and Subclasses cemia, Syncope, seizures, dysphagia, priapism, thrombotic amongst monoaminergic neurotransmitter receptors. thrombocytopenic purpura, disruption of body temperature 0015 The prevailing theory for the mechanism of action regulation, insomnia, agitation, anxiety, Somnolence, aggres of antipsychotic drugs involves antagonism of D2 sive reaction, headache, constipation, nausea, dyspepsia, receptors. Unfortunately, it is likely that antagonism of Vomiting, abdominal pain, saliva increase, toothache, rhinitis, dopamine D2 receptors also mediates the extrapyramidal side coughing, sinusitis, pharyngitis, dyspnea, back pain, chest effects as well as some additional undesired effects of antip pain, fever, rash, dry skin, seborrhea, increased upper respi sychotic therapies such as a worsening of depression symp ratory infection, abnormal vision, arthralgia, hypoaesthesia, toms, anhedonia and impairment of cognitive processes. manic reaction, concentration impairment, dry mouth, pain, Antagonism of 5-HT2A receptors is an alternate molecular fatigue, acne, pruritus, myalgia, skeletal pain, hypertension, mechanism or drugs with antipsychotic efficacy, possibly diarrhea, confusion, asthenia, urinary incontinence, sleepi through antagonism of heightened or exaggerated signal ness, increased duration of sleep, accommodation distur transduction through serotonergic systems. 5-HT2A antago bance, palpitations, erectile dysfunction, ejaculatory dys nist are therefore good candidates for treating psychosis with function, orgastic dysfunction, lassitude, increased out extrapyramidal side effects or other undesired effects pigmentation, increased appetite, automatism, increased associated with blockade of dopamine D receptors. dream activity, diminished sexual desire, nervousness, 0016 Traditionally, GPCRS such as the 5-HT2A receptor depression, apathy, catatonic reaction, euphoria, increased have been assumed to exist in a quiescent state unless acti libido, amnesia, emotional liability, nightmares, delirium, vated by the binding of an agonist (a drug that activates a yawning, dysarthria, Vertigo, stupor, paresthesia, aphasia, receptor). It is now appreciated that many, if not most, of the hypoesthesia, tongue paralysis, leg cramps, torticollis, hypo GPCR monoamine receptors, including serotonin receptors, tonia, coma, migraine, hyperreflexia, choreoathetosis, anor can exist in a partially activated State in the absence of their exia, flatulence, stomatitis, melena, hemorrhoids, gastritis, endogenous agonists. This increased basal activity (constitu fecal incontinence, erutation, gastroeophageal reflux, gastro tive activity) can be inhibited by compounds called inverse enteritis, esophagitis, tongue discoloration, choleithiasis, agonists. Both agonists and inverse agonists possess intrinsic tongue edema, diverticulitis, gingivitis, discolored feces, gas US 2015/0231126 A1 Aug. 20, 2015 trointestinal hemorrhage, hematemesis, edema, rigors, mal percentage of patients experience an efficacious effect than aise, pallor, enlarged abdomen, ascites, sarcoidosis, flushing, when the antipsychotic agent is administered alone at an hyperventilation, bronchospasm, pneumonia, tridor, asthma, efficacious dose. increased sputum, aspiration, photosensitivity, increased 0023. Another embodiment described herein includes a Sweating, acne, decreased Sweating, alopecia, hyperkerato method of reducing or preventing weight gain associated with sis, skin exfoliation, bullous eruption, skin ulceration, aggra administration of an antipsychotic agent, comprising co-ad vated psoriasis, furunculosis, Verruca, dermatitis lichenoid, ministering a 5-HT2A inverse agonist or antagonist with the hypertrichosis, genital pruritus, urticaria, Ventricular tachy antipsychotic agent to a Subject at risk of or Suffering from cardia, angina pectoris, premature atrial contractions, T wave weight gain associated with administration of an antipsy inversion, ventricular extrasystoles, ST depression, AV block, chotic agent. myocarditis, abnormal accommodation, Xerophthalmia, 0024. Another embodiment described herein includes a diplopia, eye pain, blepharitis, photopsia, photophobia, method of increasing patient compliance during antipsy abnormal lacrimation, hyponatremia, creatine phosphoki chotic therapy, comprising co-administering a 5-HT2A nase increase, thirst, weight decrease, decreased serum iron, inverse agonist or antagonist with an antipsychotic agent, cachexia, dehydration, hypokalemia, hypoproteinemia, wherein the doses of co-administration are such that patient hyperphosphatemia, hypertriglyceridemia, hyperuricemia, compliance is increased as compared to compliance when hypoglycemia, polyuria, polydipsia, hemturia, dysuria, uri administering an efficacious dose of the antipsychotic agent nary retention, cystitis, renal insufficiency, arthrosis, Synos alone. tosis, bursitis, arthritis, menorrhagia, dry vagina, nonpeurp 0025. Another embodiment described herein includes a eral lactation, amenorrhea, female breast pain, leukorrhea, method of reducing or preventing increased serum glucose mastitis, dysmenorrhea, female perineal pain, intermenstrual associated with administration of an antipsychotic agent, bleeding vaginal hemorrhage, increased SGOT, increased comprising co-administering a 5-HT2A inverse agonist or SGPT. cholestatic hepatitis, cholecystitis, choleithiasis, hepa antagonist with the antipsychotic agent to a subject at risk of titis, hepatocellular damage, epistaxis, Superficial phlebitis, or Suffering from increased serum glucose associated with thromboplebitis, thrombocytopenia, tinnitus, hyperacusis, administration of an antipsychotic agent. decreased hearing, anemia, hypochromic anemia, nor 0026. Another embodiment described herein includes a mocytic anemia, granulocytopenia, leukocytosis, lymphad method of reducing or preventing increased serum glucose enopathy, leukopenia, Pelger-Huet anomaly, gynecomastia, and reducing or preventing weight gain associated with male breast pain, antidiuretic hormone disorder, bitter taste, administration of an antipsychotic agent comprising co-ad micturition disturbances, oculogyric crisis, abnormal gait, ministering a 3-HT2A inverse agonist or antagonist with the involuntary muscle contraction, and increased injury. antipsychotic agent to a Subject at risk of or Suffering from increased serum glucose and weight gain associated with 0019. In some embodiments, the condition is psychosis administration of an antipsychotic agent. and the efficacious effect is an antipsychotic effect. In some 0027. Another embodiment disclosed herein includes a embodiments, the psychosis is associated with Schizophre pharmaceutical composition that includes a first amount of a nia. In some embodiments, the psychosis is acute psychotic 5-HT2A inverse agonist orantagonistanda second amount of exacerbation. In some embodiments, the condition amenable an antipsychotic agent, wherein the first and second amounts to treatment is selected from the group consisting of Schizo are Such that when the composition is administered, an effi phrenia, bipolar disorder, agitation, psychosis, behavioral cacious antipsychotic effect is achieved faster than when the disturbances in Alzheimer's disease, depression with psy antipsychotic agent is administered alone at an efficacious chotic features or bipolar manifestations, obsessive compul dose. In some embodiments, the second amount is less than a sive disorder, post traumatic stress syndrome, anxiety, per maximal dose of the antipsychotic agent when it is adminis Sonality disorders (borderline and Schizotypal), dementia, tered alone. In some embodiments, the second amount is less dementia with agitation, dementia in the elderly, Tourette's than an efficacious dose of the antipsychotic agent when it is syndrome, restless leg syndrome, insomnia, Social anxiety administered alone. disorder, dysthymia, ADHD, and autism. 0028. Another embodiment disclosed herein includes a 0020. Another embodiment described herein includes a package that includes a first amount of a 5-HT2A inverse method of inducing a rapid onset of an antipsychotic effect, agonist or antagonist and instructions for administering the comprising co-administering a 5-HT2A inverse agonist or first amount of the 5-HT2A inverse agonist orantagonist and antagonist and an antipsychotic agent to a Subject Suffering a second amount of an antipsychotic agent, wherein the first from psychosis Such that there is a rapid onset of antipsy and second amounts are such that an efficacious antipsychotic chotic effect. elect is achieved faster than when the antipsychotic agent is administered alone at an efficacious dose. In some embodi 0021. Another embodiment described herein includes a ments, the second amount is less than a maximal dose of the method of inducing a rapid onset of an effect, antipsychotic agent when it is administered alone. In some comprising co-administering a 5-HT2A inverse agonist or embodiments, the second amount is less than an efficacious antagonist and an antipsychotic agent to a Subject Suffering dose of the antipsychotic agent when it is administered alone. from depression Such that there is a rapid onset of antidepres 0029. In some of the above-mentioned embodiments, the sant effect. antipsychotic agent is a . In some 0022. Another embodiment described herein includes a embodiments, the antipsychotic agent is an atypical antipsy method of increasing the percentage of patients responding to chotic. In some embodiments, the antipsychotic agent is a D2 antipsychotic therapy, comprising co-administering a antagonist. In some embodiments, the antipsychotic agent is 5-HT2A inverse agonist or antagonist and an antipsychotic risperidone. In some embodiments, the antipsychotic agent is agent to a subject Suffering from psychosis such that a greater . In some embodiments, the antipsychotic agent is US 2015/0231126 A1 Aug. 20, 2015

selected from the group consisting of a , a phe -continued nylbutylpiperidine, a dibenzapine, a benzisoxidil, and a salt F of lithium. In some embodiments, the phenothiazine is selected from the group consisting of (Thora zine(R), (Serentil(R), (Com pazine(R), (Mellaril), (Prolixin R), (Trilafon(R), and (Stelazine(R). In Some embodiments, the phenylbutylpiperidine is (Orap(R). In some embodiments, the dibenzapine is selected from the group consisting of (CloZaril(R), (Loxitane(R), (ZyprexaR), and (Sero quel(R). In some embodiments, the benzisoxidil is Ziprasi done (Geodon(R). In some embodiments, the salt of lithium is lithium carbonate. In some embodiments, the antipsychotic 0033. In still other embodiments, the 5-HT2A inverseago agent is selected from the group consisting of nist or antagonist is selected from the group consisting of (Abilify(R), Etrafon R, (Inapsine(R). Thioridazine , , Benanserin, , (MellarilR). Thiothixene (Navane(R). (Phener Butanserin, , , , Fli gan.R.), (ReglanR), (Tarac banserin, , Iferanserin, Katanserin, Lidaserin, tan.R.), Triavil(R), Molindone (Moban(R), (Ser , , , , Seganserin, lect(R), Droperidol, (SolianR), , and Tropanserin. (InvegaR), and Tetrabenazine. 0034. In some of any of the above-mentioned methods, the 0030. Another embodiment described herein includes a administration is to a human less than eighteen years of age. method of reducing or preventing hyperprolactinemia caused 0035 Another embodiment described herein includes a by administration of risperidone, comprising co-administer method of treatment that includes determining that a first ing a 5-HT2A inverse agonist or antagonist with less than 6 pharmaceutical agent modulates a pharmacological property mg per day of risperidone to a subject at risk of or Suffering of a second pharmaceutical agent, determining that the first from hyperprolactinemia associated with administration of pharmaceutical agent has a longer half-life than a second risperidone. pharmaceutical agent, and co-administering the first and sec ond pharmaceutical agent to a patient. In some embodiments, 0031. In some of any of the above-mentioned embodi the pharmacological property is receptor occupancy. In some ments, the 5-HT2A inverse agonist or antagonist is the com embodiments, the pharmacological property is the minimum pound of formula (I): efficacious dose of the second pharmaceutical agent. In some embodiments, the half-life of the first agent is at least about 1.5 times higher than the half-life of the secondagent. In some (I) embodiments, the co-administration results in the second CH3 agent being present at an efficacious level during at least about 50% of the time between successive dosing of the second agent. In some embodiments, the co-administration results in the second agent being present at an efficacious level during substantially all of the time between successive dosing of the second agent and wherein said second agent would not have been present at an efficacious level for sub stantially all of the period between successive dosing if first agent had been administered alone with the same dosing to or schedule and dosage. In some embodiments, the first phar macological agent and said second pharmacological agent are administered at doses and time intervals which result in said 0032. In other embodiments, the 5-HT2A inverse agonist second pharmacological agent being present at an efficacious or antagonist is a compound selected from the group consist level for a period of time which is longer than the period of ing of time which said second therapeutic agent would be present at an efficacious level if said second therapeutic agent had been administered alone. 0036) Another embodiment described herein includes a method of determining whether a test therapeutic agent is a good candidate for combination therapy with a therapeutic agent having a first half-life comprising obtaining a test thera peutic agent having a second half-life that is longer than said first half-life and evaluating whether administering said test therapeutic agent in combination with said therapeutic agent allows said therapeutic agent to be efficacious at a level at which it is not efficacious when administered alone. Some O embodiments include determining whether said test thera and peutic agent enhances a level of receptor occupancy, wherein said receptor is targeted by said therapeutic agent. US 2015/0231126 A1 Aug. 20, 2015

BRIEF DESCRIPTION OF THE DRAWINGS Vanserin in combination with risperidone in a dizocilpine induced hyperlocomotor assay. 0037 FIG. 1A is a graph depicting the drug level and 0056 FIG. 14B is a graph depleting an isobologram that therapeutic window for single agent administration. demonstrates Synergism upon administration of risperidone 0038 FIG. 1B is a graph depicting the drug level and in combination with pimavanserin. therapeutic window for co-administration of two drugs hav 0057 FIG. 15A is graph illustrating the distance traveled ing similar half lives. by mice in an -induced hyperlocomotor assay 0039 FIG. 1C is a graph depicting the drug level and upon administration of pimavanserin, aripiprazole, or pima therapeutic window for co-administration of two drugs have Vanserin in combination with aripiprazole. different half lives. 0.058 FIG. 15B is a graph illustrating dose response 0040 FIG. 2 is a graph depicting change in PANSS score curves for administration to mice of pimavanserin, aripipra upon administration of risperidone and haloperidol alone and Zole, or pimavanserin in combination with aripiprazole in an in combination with pimavanserin. amphetamine-induced hyperlocomotor assay. 0041 FIGS. 3A and 3B are bar graphs deploring the per cent of responded to therapy with risperidone and haloperidol 0059 FIG.16A is a graph illustrating the distance traveled alone and in combination with pimavanserin at Day 15 and by mice in an amphetamine-induced hyperlocomotor assay Day 43, respectively. upon administration of pimavanserin, quetiapine, or pima 0042 FIGS. 4A and 4B are graphs depicting change in Vanserin in combination with quetiapine. PANSS positive and negative scales, respectively, upon 0060 FIG. 16B is a graph illustrating dose response administration of risperidone and haloperidol alone and in curves for administration to mice of pimavanserin, quetiap combination with pimavanserin. ine, or pimavanserin in combination with quetiapine in an 0043 FIGS. 5A and 5B are graphs depicting change in amphetamine-induced hyperlocomotor assay. PANSS psychopathology and cognition scales, respectively, 0061 FIG. 17 is a graph depicting an isobologram that upon administration of risperidone and haloperidol alone and demonstrates additivity upon administration of quetiapine in in combination with pimavanserin. combination with pimavanserin. 0044 FIG. 6 is a graph depicting change in the CGI 0062 FIG. 18 is a bar graph depicting percent novel object severity Scale upon administration of risperidone and halo recognition upon administration of vehicle, pimavanserin, peridol alone and in combination with pimavanserin. risperidone, olanzapine, and combinations of pimavanserin 0045 FIG. 7A is a bar graph depicting the percent of with risperidone or olanzapine in a novel object recognition Subjects experiencing weight gain upon administration of assay. risperidone and haloperidol alone and in combination with 0063 FIG. 19 is a graph depicting working memory errors pimavanserin. after repeated trials upon administration of vehicle, risperi 0046 FIG. 7B is a bar graph depicting the mean weight done, pimavanserin, and combinations of risperidone with gain in Subjects upon administration of risperidone and halo pimavanserin in a radial arm maze in vivo mouse model of peridol alone and in combination with pimavanserin. cognition. 0047 FIGS. 8A and 8B are graphs depicting change in 0064 FIG. 20A is a graph depicting serum prolactin levels prolactin levels in males and females, respectively, upon upon administration of risperidone, haloperidol, or pimavan administration of risperidone and haloperidol alone and in serin. combination with pimavanserin. 0065 FIG. 20B is a bar graph depicting serum prolactin 0048 FIG. 9 is a bar graph depicting glucose levels upon levels upon administration of pimavanserin in combination administration of risperidone alone and in combination with with risperidone or haloperidol. pimavanserin. 0.066 FIGS. 21A and 21B depict dose response curves for 0049 FIG. 10 is a graph depicting the percent of respond haloperidol- and risperidone-induced catalepsy in rats, ers to therapy with risperidone or haloperidol, alone or in respectively, upon administration of pimavanserin. combination with pimavanserin. 0067 FIG. 22 is a graph depicting mean changes in pro 0050 FIG. 11 is a graph depicting the percent of respond lactin levels upon administration of risperidone alone and in ers to therapy with risperidone alone or in combination with combination with pimavanserin. pimavanserin. 0068 FIG. 23 is a graph depicting plasma concentration of 0051 FIG. 12A is graph depicting the distance traveled by risperidone and pimavanserin upon daily individual adminis mice in an amphetamine-induced hyperlocomotor assay upon tration. administration of pimavanserin, haloperidol, orpimavanserin 0069 FIG. 24 is a graph depicting 5-HT2A and D2 recep in combination with haloperidol. toroccupancy upon daily individual administration of risperi 0052 FIG.12B is a graph depicting dose response curves done and pimavanserin. for administration to mice of pimavanserin, haloperidol, or (0070 FIG.25 is a graph depicting 5-HT2A and D2 recep pimavanserin in combination with haloperidol in an amphet tor occupancy upon daily administration of pimavanserin in amine-induced hyperlocomotor assay. combination with 1 mg of risperidone. 0053 FIG. 13A is a graph depicting dose response curves (0071 FIGS. 26A and 26B are graphs depicting 5-HT2A for administration to mice of pimavanserin, haloperidol, or and D2 receptor occupancy upon administration of 3 mg pimavanserin in combination with haloperidol in a dizo risperidone twice daily alone (FIG. 26A) and in combination cilpine-induced hyperlocomotor assay. (FIG. 26B) with pimavanserin excluding the contribution 0054 FIG. 13B is a graph depicting an isobologram that from paliperidone. demonstrates Synergism upon administration of haloperidol (0072 FIGS. 27A and 27B are graphs depicting 5-HT2A in combination with pimavanserin. and D2 receptor occupancy for paliperidone upon adminis 0055 FIG. 14A is a graph depicting response curves for tration of 3 mg risperidone twice daily alone (FIG. 27A) and administration to mice of pimavanserin, risperidone, or pima in combination (FIG. 27B) with pimavanserin. US 2015/0231126 A1 Aug. 20, 2015

0073 FIGS. 28A and 28B are graphs depleting 5-HT2A above to take effect. While not being bound by any particular and D2 receptor occupancy upon administration of 3 mg theory, it is believed that if the dosage of the antipsychotic risperidone twice daily alone (FIG. 28A) and in combination agent is too high, resulting in high D2 antagonistic activity, (FIG. 28B) with pimavanserin including the contribution then the regional modulation of D2 antagonism described from paliperidone. above will not have a significant efficacious effect. 0074 FIGS. 29A and 29B are graphs depicting 5-HT2A and D2 receptor occupancy upon administration of 1 mg 0080. In some embodiments, the co-administration risperidone twice daily alone (FIG.29A) and in combination described herein eliminates or reduces the severity of one or (FIG. 29B) with pimavanserin excluding the contribution more side effects caused by the antipsychotic when it is from paliperidone. administered alone at an efficacious dose. In various embodi 0075 FIGS. 30A and 30B are graphs depicting 5-HT2A ments, the side effects are selected from the group consisting and D2 receptor occupancy upon administration of 1 mg of stroke, tremors, sedation, gastrointestinal problems, neu risperidone twice daily along (FIG.30A) and in combination rological problems, increased risk of death, cerebrovascular (FIG. 30B) with pimavanserin including the contribution events, movement disorder, dystonia, akathisia, parkinso from paliperidone. niam movement disorder, tardive dyskinesia, cognitive disor 0076 FIGS. 31A and 31B are graphs depicting 5-HT2A ders, prolactinemia, catalepsy, psychosis, neuroleptic malig and D2 receptor occupancy upon administration of 1 mg nant syndrome, heart problems, pulmonary problems, diabetes, liver failure, suicidality, sedation, orthostatic risperidone twice daily along (FIG.31A) and in combination hypotension, choking, dizziness, tachycardia, blood abnor (FIG. 31B) with pimavanserin including the contribution malities (including abnormal triglyceride levels, increased from paliperidone. cholesterol levels, dyslipidemia, and hyperglycemia), Syn DETAILED DESCRIPTION OF CERTAIN cope, seizures, dysphagia, priapism, thrombotic thrombocy EMBODIMENTS topenic purpura, disruption of body temperature regulation, insomnia, agitation, anxiety, Somnolence, aggressive reac 0.077 Some embodiments include the co-administration tion, headache, constipation, nausea, dyspepsia, Vomiting, of a 5-HT2A inverse agonist or antagonist along with an abdominal pain, saliva increase, toothache, rhinitis, cough antipsychotic agent. In some embodiments, the 5-HT2A ing, sinusitis, pharyngitis, dyspnea, back pain, chest pain, inverse agonist or antagonist enhances the efficacy of the fever, rash, dry skin, seborrhea, increased upper respiratory antipsychotic agent while decreasing the side effects caused infection, abnormal vision, arthralgia, hypoaesthesia, manic by the antipsychotic agent. While not being bound by any reaction, concentration impairment, dry mouth, pain, fatigue, particular theory, it is believed that the 5-HT2A inverse ago acne, pruritus, myalgia, skeletal pain, hypertension, diarrhea, nist orantagonist can modulate the D2 antagonistic activity of confusion, asthenia, urinary incontinence, sleepiness, the antipsychotic agent. Specifically, it is believed that the increased duration of sleep, accommodation disturbance, pal 5-HT2A inverse agonist or antagonist enhances the D2 pitations, erectile dysfunction, ejaculatory dysfunction, antagonistic activity in regions of the brain responsible for orgastic dysfunction, lassitude, increased pigmentation, psychotic effects (e.g., hallucinations) while at the same time increased appetite, automatism, increased dream activity, diminishing D2 antagonistic activity in regions of the brain diminished sexual desire, nervousness, depression, apathy, which cause adverse side effects (e.g., cognitive impairment, catatonic reaction, euphoria, increased libido, amnesia, emo depression, and extrapyrmaidal side effects). These two tional liability, nightmares, delirium, yawning, dysarthria, actions, decreasing undesired effects of D2 receptor blockade Vertigo, stupor, paresthesia, aphasia, hypoesthesia, tongue in brain regions associated with motoric control or cognitive paralysis, leg cramps, torticollis, hypotonia, coma, migraine, function, while simultaneously increasing the effectiveness hyperreflexia, choreoathetosis, anorexia, flatulence, Stomati of the desired antipsychotic actions will result in increased tis, melena, hemorrhoids, gastritis, fecal incontinence, eruta antipsychotic efficacy with diminished side effects. tion, gastroesophageal reflux, gastroenteritis, esophagitis, 0078. By “co-administration” or administration “in com tongue discoloration, choleithiasis, tongue edema, diverticu bination, it is meant that the two or more agents may be litis, gingivitis, discolored feces, gastrointestinal hemor found in the patient’s bloodstream at the same time, regard rhage, hematemesis, edema, rigors, malaise, pallor, enlarged less of when or how they are actually administered. In one abdomen, ascites, sarcoidosis, flushing, hyperventilation, embodiment, the agents are administered simultaneously. In bronchospasm, pneumonia, tridor, asthma, increased sputum, one such embodiment, administration in combination is aspiration, photosensitivity, increased Sweating, acne, accomplished by combining the agents in a single dosage decreased Sweating, alopecia, hyperkeratosis, skin exfolia form. In another embodiment, the agents are administered tion, bullous eruption, skin ulceration, aggravated psoriasis, sequentially. In one embodiment the agents are administered furunculosis, Verruca, dermatitis lichenoid, hypertrichosis, through the same route. For example, in Some embodiments, genital pruritus, urticaria, Ventricular tachycardia, angina both agents are administered orally. In another embodiment pectoris, premature atrial contractions, T wave inversion, the agents are administered through different routes. For ventricular extrasystoles, ST depression, AV block, myo example, in one embodiment, one agent is administered carditis, abnormal accommodation, Xerophthalmia, diplopia, orally and the other agent is administered i.v. eye pain, blepharitis, photopsia, photophobia, abnormal lac 0079. In some embodiments, use of the 5-HT2A inverse rimation, hyponatremia, creatine phosphokinase increase, agonist or antagonist allows the dose of the antipsychotic thirst, weight decrease, decreased serum iron, cachexia, agent to be reduced. This reduction results in an elimination dehydration, hypokalemia, hypoproteinemia, hyperphos or reduction in the severity of side effects caused by the phatemia, hypertrigylceridemia, hyperuricemia, hypoglyce antipsychotic agent. In addition, in some embodiments, mia, polyuria, polydipsia, hemturia, dysuria, urinary reten reduction of the dosage of the antipsychotic agent allows the tion, cystitis, renal insufficiency, arthrosis, Synostosis, beneficial regional modulation of D2 antagonism described bursitis, arthritis, menorrhagia, dry vagina, nonpeurperallac US 2015/0231126 A1 Aug. 20, 2015

tation, amenorrhea, female breast pain, leukorrhea, mastitis, toms of a neuropsychiatry disorder, including but not limited dysmenorrhea, female perineal pain, intermenstrual bleed to schizophrenia, Schizoaffective disorders, mania, depres ing, vaginal hemorrhage, increased SGOT, increased SGPT. sion (including dysthymia, treatment-resistant depression, cholestatic hepatitis, cholecystitis, choleithiasis, hepatitis, and depression associated with psychosis), cognitive disor hepatocellular damage, epistaxis, Superficial phlebitis, ders, aggressiveness (including impulsive aggression), panic thromboplebitis, thrombocytopenia, tinnitus, hyperacusis, attacks, obsessive compulsive disorders, borderline person decreased hearing, anemia, hypochromic anemia, nor ality disorder, borderline disorder, multiplex developmental mocytic anemia, granulocytopenia, leukocytosis, lymphad disorder (MDD), behavioral disorders (including behavioral enopathy, leucopenia, Pelger-Huet anomaly, gynecomastia, disorders associated with age-related dementia), psychosis male breast pain, antidiuretic hormone disorder, bitter taste, (including psychosis associated with dementia, psychosis micturition disturbances, oculogyric crisis, abnormal gait, associated with Parkinson's disease, psychosis associated involuntary muscle contraction, and increased injury. In one with Alzheimer's disease, induced by treatment, such as treat embodiment, the side effect is weight gain. In one embodi ment of Parkinson's disease, or associated with post trau ment, side effect is associated with administration of the matic stress disorder), Suicidal tendency, bipolar disorder, antipsychotic to a child under 18. In one embodiment, the side sleep disorder (including sleep maintenance insomnia, effect in the child is selected from psychosis, schizophrenia, chronic insomnia, transient, insomnia, and periodic limb pervasive developmental disorder, autism, Tourette’s Syn movements during sleep (PLMS)), addiction (including drug drome, conduct disorder, aggression, attention and hyperac or addiction, opioid addiction, and nicotine addic tivity difficulties (e.g., ADD, ADHD). In some embodiments, tion), attention deficit hyperactivity disorder (ADHD), post the side effects of weight gain, heart rhythm problems, and traumatic stress disorder (PTSD), Tourette's syndrome, anxi diabetes are more severe in children. ety (including general anxiety disorder (GAD)), autism, 0081. In some embodiments, due to decreased side effects, Down's syndrome, learning disorders, psychosomatic disor the co-administration described herein can be used to ders, alcohol withdrawal, epilepsy, pain (including chronic increase patient compliance during antipsychotic therapy. pain, neuropathic pain, inflammatory pain, diabetic periph 0082 In some embodiments, the antipsychotic agent is eral neuropathy, fibromyalgia, postherpetic neuralgia, and administered at a sub-maximal level. In various such embodi reflex sympathetic dystrophy), disorders associated with ments, the dosage of the antipsychotic agent is less than about hypoglutamatergia (including Schizophrenia, childhood 75%, 60%, 30%, 40%, 30%, 20%, or 10% of the maximal autism, and dementia), and serotonin syndrome. dose. By "maximal dose, it is meant the minimum dose 0085. In some embodiments, the co-administration of the where further increases in the dose do not result in any sig 5-HT2A inverse agonist or antagonist with the antipsychotic nificant increase in therapeutic effect when administering the agent is used to treat, prevent, or ameliorate the symptoms of agent alone. In some embodiments, the antipsychotic agent is a neurodegenerative disorder, including but not limited to administered at a dose that is less than an efficacious dose for Alzheimer's disease, Parkinson's disease, Huntington's cho the antipsychotic when it is administered alone. In various rea, sphinocerebellar atrophy, frontotemporal dementia, embodiments, the dosage is less than about 75%, 60%, 50%, Supranuclear palsy, or Lewy body dementia. 40%, 30%, 20%, or 10% of an efficacious dose. By “effica 0086. In some embodiments, the co-administration of the cious dose' it is meant the minimal dosage that is required to 5-HT2A inverse agonist or antagonist with the antipsychotic achieve a clinically relevant therapeutic effect when admin agent is used to treat, prevent, or ameliorate the symptoms of istering foe agent alone. an extrapyramidal disorder including, but not limited to, dys 0083. In some embodiments, co-administration of the kinesias (such as induced by treatment of Parkinson's dis 5-HT2A inverse agonist or antagonist with the antipsychotic ease), bradykinesia, rigidity, psychomotor slowing, tics, agent results in a rapid onset of an efficacious effect. In other akathisia (such as induced by a neuroleptic or SSRI agent), words, in Some embodiments, efficacious activity is achieved Friedrich's ataxia, Machado-Joseph’s disease, dystonia, faster than when the antipsychotic agent is administered tremor, restless legs syndrome, or myoclonus. alone. In various embodiments, the rapid onset of efficacious 0087. In some embodiments, the co-administration of the activity is demonstrated by a clinically relevant therapeutic 5-HT2A inverse agonist or antagonist with the antipsychotic effect being achieved greater than about 30%, 40%, 50%, agent is used to treat, prevent, or ameliorate the symptoms of 60%, 70%, 80%, 90%, 100%, 110%, 130%, 150%, 200%, chemotherapy-induced emesis, frailty, on/off phenomena, 300%, 400%, or 300% faster than when the antipsychotic non-insulin-dependent diabetes mellitus, metabolic Syn agent is administered alone at an efficacious dose. In some drome, autoimmune disorders (including lupus and multiple embodiments, the rapid onset of efficacious activity is dem Sclerosis), sepsis, increased intraocular pressure, glaucoma, onstrated by a greater percentage of patients experiencing an retinal diseases (including age related macular degeneration), efficacious effect after a specified period of time of therapy Charles Bonnet syndrome. Substance abuse, sleep apnea, pan when compared to administration of the antipsychotic agent creatis, anorexia, bulimia, disorders associated with alcohol alone at an efficacious dose. In various embodiments, the ism, cerebral vascular accidents, amyotrophic lateral sclero percentage of patients experiencing an efficacious effect is sis, AIDS related dementia, traumatic brain or spinal injury, increased by greater than about 20%, 30%, 40%, 50%, 60%, tinnitus, menopausal symptoms (such as hot flashes), sexual 70%, 80%, 90%, 100%, 110%, 130%, 130%, 200%, 300%, dysfunction (including female sexual dysfunction, female 400%, or 500% when compared to administration of the sexual arousal dysfunction, hypoactive sexual desire disor antipsychotic agent alone at an efficacious dose. In some der, decreased libido, pain, aversion, female orgasmic disor embodiments, the specified period of time is two weeks. der, and ejaculatory problems), low male fertility, low sperm 0084. In various embodiments, the co-administration of motility, hair loss or thinning, incontinence, hemorrhoids, the 5-HT2A inverse agonist or antagonist with the antipsy migraine, hypertension, thrombosis (including thrombosis chotic agent is used to treat, prevent, or ameliorate the Symp associated with myocardial infarction, stroke, idiopathic US 2015/0231126 A1 Aug. 20, 2015

thrombocytopenic purpura, thrombotic thrombocytopenic 0092. In some embodiments, the 5-HT2A inverse agonist purpura, and peripheral vascular disease), abnormal hor orantagonist is selective for the 5-HT2A receptor. By “selec monal activity (such as abnormal levels of ACTH, corticos tive it is meant that an amount of the compound Sufficient to terone, rennin, or prolactin), hormonal disorders (including effect the desired response from the 5-HT2A receptor has Cushing's disease. Addison's disease, and hyperprolactine little or no effect upon the activity of other certain receptor mia), a pituitary tumor (including a prolactinoma), a side types, subtypes, classes, or Subclasses. In some embodi effect associated with a pituitary tumor (including hyperpro ments, the 5-HT2A inverse agonist or antagonist does not lactinemia, infertility, changes in menstruation, amenorrhea, interact strongly with other serotonin receptors (5-HT1A, galactorrhea, loss of libido, vaginal dryness, osteoporosis, 1B, 1D, 1E, 2B, , 4C, 6, and 7) at concentrations where the impotence, headache, blindness, and double vision), vasos signaling of the 5-HT2A receptor is strongly or completely pasm, ischemia, cardiac arrythmias, cardiac insufficiency, inhibited. In some embodiments, the 5-HT2A inverse agonist asthma, emphysema, or appetite disorders. or antagonist is selective with respect to other monoamine 0088. In some embodiments, the co-administration is used binding receptors, such as the dopaminergic, histaminergic, to treat, prevent, or ameliorate psychosis. Functional causes adrenergic and muscarinic receptors. In some embodiments, of the psychosis may include schizophrenia, Parkinson's dis the 5-HT2A inverse agonist or antagonist has little or no ease, Alzheimer's disease, bipolar disorder, severe clinical activity at D2 receptors. depression, severe psychosocial, stress, sleep deprivation, 0093. In various embodiments, the 5-HT2A inverse ago neurological disorders including brain, tumor, dementia with nist or antagonist is selected from the group consisting of Lewy bodies, multiple Sclerosis, and sarcoidosis, electrolyte Adatanserin Hydrochloride. Altanserin Tartrate, Benanserin disorders including hypocalcemia, hypernatremia, hyonatre Hydrochloride, Blonanserin, Butanserin, Cinanserin Hydro mia, hyopkalemia, hypomagnesemia, hypermagnesemia, chloride, Eplivanserin, Fananserin, , Gle hypercalcemia, hypophosphatemia, and hypoglycemia, manserin, Iferanserin, , , Mianserin lupus, AIDS, leprosy, malaria, flu, mumps, psychoactive drug Hydrochloride, Pelanserin Hydrochloride, Pruvanserin, intoxication or withdrawal including alcohol, barbiturates, Ritanserin, Seganserin, Tropanserin Hydrochloride, Iloperi benzodizepeines, anticholinergics, atropine, Scopolamine, done, Sertindole, EMR-62218, Org-5222, , asenap Jimson weed, , cocaine, , and ine, , APD125, and AVE8488. hallucinogens including cannabis, LSD, , mesca 0094. In some embodiments, the 5-HT2A inverse agonist line, MDMA, and PCP. Psychosis may include symptoms or antagonist is selected from a compound disclosed in U.S. such as delusions, hallucinations, disorganized speech, dis Pat. Nos. 6,756,393, 6,911,452; or 6,358,698 or U.S. Appli organized behavior, gross distortion of reality, impaired men cation Publication No. 2004-0106600, all of which are incor tal capacity, impaired affective response, fluctuating level of porated herein by reference in their entirety. In some embodi consciousness, poor motor co-ordination, inability to per ments, the 5-HT2A inverse agonist or antagonist is selected form simplemental tasks, disorientation as to person, place or from one of the following structures or prodrugs, metabolites, time, confusion, or memory impairment. In one embodiment, hydrates, Solvates, polymorphs, and pharmaceutically the patient is experiencing acute exacerbation of psychosis. acceptable salts thereof: The rapid onset characteristics of certain combinations described herein are particularly advantageous in treating acute exacerbation of psychosis. In some embodiments, the combination is used to treat or ameliorate Schizophrenia and specifically, psychosis associated with Schizophrenia. In one embodiment, the patient has exhibited a prior response to antipsychotic therapy. In one embodiment, the patient exhib its a moderate degree of psychopathology. 0089. In one embodiment, the co-administration is used to treat depression. In one embodiment, the co-administration results in a rapid onset of antidepressant activity as compared to the onset of activity observed with typical (e.g., SSRIs). In various embodiments, efficacious antide pressant activity is achieved in less than about 8 weeks, 6 weeks, 4 weeks, or 2 weeks. 0090. Many antipsychotic agents increase serum glucose levels. It has been surprisingly discovered that combination of a 5-HT2A inverse agonist with Such an antipsychotic results in a decreased serum glucose elevation while maintaining efficacy. Accordingly, in various embodiments, the co-admin istration of the 5-HT2A inverse agonist orantagonist with the antipsychotic agent is used to prevent or reduce increased serum glucose associated with administration of the antipsy chotic agent. 0.091 Many antipsychotic agents also cause weight gain. In some embodiments, the co-administration of the 5-HT2A 0095. In one embodiment, the 5-HT2A inverse agonist or inverse agonist or antagonist with the antipsychotic agent is antagonist is pimavanserin or prodrugs, metabolites, used to prevent or reduce increased weight gain associated hydrates, Solvates, polymorphs, and pharmaceutically with administration of the antipsychotic agent. acceptable salts thereof. Pimavanserin, which is also known US 2015/0231126 A1 Aug. 20, 2015 as N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)- ventional procedures for the selection and preparation of N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide, N-(4- Suitable prodrug derivatives are described, for example, in fluorophenyl)methyl-N-(1-methyl-4-piperidinyl)-N'-4- Design of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985), (2-methylpropoxy)phenylmethyl-urea, 1-(4-fluorobenzyl)- which is hereby incorporated herein by reference in its 1-(1-methylpiperidin-4-yl)-3-4-(2-methylpropoxy)benzyl entirety. urea, or ACP-103 has the structure of Formula (I): 0.098 Metabolites include active species that are produced upon introduction of the parent compound into the biological milieu. (I) (0099. The term “pharmaceutically acceptable salt” refers CH to a salt of a compound that does not cause significant irrita tion to an organism to which it is administered and does not abrogate the biological activity and properties of the com pound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), Sulfuric acid, nitric acid, phosphoric acid and the like. Pharmaceutical salts can also be obtained by reacting a compound with an to or organic acid such as aliphatic or aromatic carboxylic or Sul fonic acids, for example acetic, Succinic, lactic, malic, tar 0.096 Pimavanserin can be obtained in a number of salts taric, citric, ascorbic, nicotinic, methanesulfonic, ethane and crystalline forms. Exemplary salts include the tartrate, Sulfonic, p-toluenSulfonic, Salicylic or naphthalenesulfonic hemi-tartrate, curate, fumarate, maleate, malate, phosphate, acid. Pharmaceutical salts can also be obtained by reacting a Succinate, Sulphate, and edisylate (ethanedisulfonate) salts. compound with a base to form a salt such as an ammonium Pimavanserin salts including the aforementioned ions, among salt, an alkali metal salt, such as a sodium or a potassium salt, others, are described in U.S. Patent Publication No. 2006 an alkaline earth metal salt, Such as a calcium or a magnesium 01 11399, filed Sep. 26, 2005 and entitled “SALTS OF N-(4- salt, a salt of organic bases such as dicyclohexylamine, N-me FLUOROBENZYL)-N-(1-METHYLPIPERIDIN-4-YL)- thyl-D-glucamine, tris(hydroxymethyl)methylamine, C-C, N'-(4-(2-METHYLPROPYLOXY)PHENYLMETHYL) alkylamine, cyclohexylamine, triethanolamine, ethylenedi CARBAMDE AND THEIR PREPARATION” which is amine, and salts with amino acids such as arginine, , and incorporated herein by reference in its entirety. Several crys the like. talline forms of the tartrate salt are referred to as crystalline 0100 If the manufacture of pharmaceutical formulations Form A, Form B, Form C Form D, Form F, and Form F, and involves intimate mixing of the pharmaceutical excipients are described in U.S. Patent Publication No. 2006-0106063, and the active ingredient in its salt form, then it may be filed Sep. 26, 2006 and entitled “SYNTHESIS OF N-(4- desirable to use pharmaceutical excipients which are non FLUOROBENZYL)-N-(1-METHYLPIPERIN-4-YL)-N'- basic, that is, either acidic or neutral excipients. (4-(2-METHYL PROPYLOXY)PHENYLMETHYL)CAR 0101 Pimavanserin exhibits activity at monoamine recep BAMIDE AND ITS TARTRATE SALT AND tors, specifically serotonin receptors and specifically acts as CRYSTALLINE FORMS,” which is incorporated herein by an inverse agonist at the 5-HT2A receptor. The compound reference in its entirety in an embodiment, the crystalline shows high potency as an inverse agonist (and competitive form of the tartrate salt of pimavanserin is Form A. In another antagonist) at the 5HT receptor using a cell-based in vitro embodiment, the crystalline form of the tartrate salt of pima functional assay as well as using radioligand-binding assays. Vanserin is Form C. Pimavanserin (including, for example, The compound exhibits lesser potency at 5-HT, receptors as the tartrate salt) may be formulated into tablets, such as is an inverse agonist (and competitive antagonist) using a cell described in more detail in U.S. Patent Publication Nos. based functional assay and in radioligand-binding assays. 2007-0260064, filed May 15, 2007 and 2007-0254330, filed The compound lacks activity at dopamine receptor Subtypes. May 15, 2007, each entitled “PHARMACEUTICAL FOR Unlike existing atypical antipsychotics, pimavanserin does MULATIONS OF PIMAVANSERIN,” which art incorpo not have significant potency for a variety of other targets that rated herein by reference in their entireties. have been implicated in a range of dose-limiting side effects 0097. A “prodrug” refers to an agent that is converted into of the other antipsychotic drugs. For example, unlike cloza the parent drug in vivo. Prodrugs are often useful because, in pine and olanzapine, pimavanserin does not have significant Some situations, they may be easier to administer than the activity at the muscarinic and histaminergic receptors that parent drug. They may, for instance, be bioavailable by oral mediate sedation and potentially weight gain. The compound administration whereas the parent is not. The prodrug may also lacks the alpha-adrenergic antagonist activities of cloza also have improved solubility in pharmaceutical composi pine, olanzapine, risperidone, and that may con tions over the parent drug. An example, without limitation, of tribute to cardiovascular side effects. Further, the compound a prodrug would be a compound which is administered as an lacks potency at the 5TH receptor that controls gastrointes ester (the “prodrug) to facilitate transmittal across a cell tinal function and myocardial development. membrane where water solubility is detrimental to mobility 0102 Pimavanserin is active in a number of models but which then is metabolically hydrolyzed to the carboxylic thought to be predictive of antipsychotic activity such as DOI acid, the active entity, once inside the cell where water-solu ((+)-2,5-dimethoxy-4-iodoamphetamine, a serotonin ago bility is beneficial. A further example of a prodrug might be a nist) induced head twitches in the rat and attenuation of short peptide (polyaminoacid) bonded to an acid group where hyperactivity in mice induced by the N-methyl-D-aspartate the peptide is metabolized to reveal the active moiety. Con antagonist MK-801. The compound was effective in these US 2015/0231126 A1 Aug. 20, 2015 10 models at oral doses of 3 and 10 mg/kg. In a rat model of deficits in sensory motor gating similar to those exhibited by Schizophrenics, pimavanserin at doses of 1 and 3 mg/kg SC potently reversed the gating deficit induced by DOI. Pima Vanserin also failed to disrupt learning of a simple auto shaped response in mice at intraperitoneal doses up to 32 mg/kg. The pharmacological profile of pimavanserin Sug gests it will be effective as antipsychotic agent without the side effects common to other compounds in this class. Thus, pimavanserin will have antipsychotic activity when used to treat Schizophrenic Subjects. 0103 Pimavanserin may be synthesized by methods described below, or by modification of these methods. Ways of modifying the methodology include, among others, modi (IV) fication in temperature, Solvent, reagents, etc. 0107 The compound of formula (V) is heated to reflux 0104. The first step of the synthesis, illustrated below, is with diphenylphosphonyl azide (DPPA) and a proton sponge conducted In the presence of acetic acid, NaBHCN, and in tetrahydrofuran (THF) to produce the compound of for methanol to produce the compound of formula (II): mula (VI):

O NaBH3CN NCO N HOAc OH MeOH -- -e- DPPA Proton Sponge THF -er reflux O

F u? 1. (VI) (V) OUI 0.108 Finally, reaction of the compound of formula (II) (II) with the compound of formula (VI) in methylene chloride produces the compound of formula (I): 0105. The compound of formula (IV) can be synthesized by treatment of the compound of formula (III) with isobutyl NCO bromide and potassium carbonate in dimethyl formamide (DMF) at about 80° C.: N

O F -- He O o1 C CHCl2 o1 NH i-BuBr (II) K2CO3 u? DMF (VI) -e- 80° C. O OH (III) F - (IV)

0106 The compound of formula (IV) can be converted to O the compound of formula (V) by reaction with potassium (I) hydroide in methanol/water: US 2015/0231126 A1 Aug. 20, 2015

0109) Non-limiting examples of suitable antipsychotic aliphatic , and the like may be used as Surface active agents that may be co-administered with a 5-HT2A inverse agents. Sucrose, glucose, lactose, starch, crystallized cellu agonist or antagonist include a phenothiazine, a phenylbu lose, mannitol, light anhydrous silicate, magnesium alumi tylpiperidine, a dibenzapine, a benzisoxidil, and a salt of nate, magnesium methasilicate aluminate, synthetic alumi lithium. In some embodiments, the phenothiazine is selected num silicate, calcium carbonate, sodium acid carbonate, from the group consisting of chlorpromazine (Thorazine(R). calcium hydrogen phosphate, calcium carboxymethyl cellu mesoridazine (Serentil(R), prochloperazine (Compazine(R). lose, and the like may be used as exciptents; magnesium thioridazine (Mellaril), Fluphenazine (Prolixin R), Perphena Stearate, talc, hardened oil and the like maybe used as Smooth zine (TrilafonR), and Trifluoperazine (Stelazine(R). In some ing agents; coconut oil, olive oil, Sesame oil peanut oil, Soya embodiments, the phenylbutylpiperidine is selected from the may be used as Suspension agents or lubricants; cellulose group consisting of haloperidol (Haldol(R) and pimozide acetate phthalate as a derivative of a carbohydrate Such as (Orap(R). In some embodiments, the dibenzapine is selected cellulose or Sugar, or methylacetate-methacrylate copolymer from the group consisting of clozapine (CloZaril(R), loxapine as a derivative of polyvinyl may be used as Suspension agents; (Loxitane(R), olanzapine (ZyprexaR), and quetiapine (Sero and plasticizers such as ester phthalates and the like may be quel(R). In some embodiments, the benzisoxidil is selected used as Suspension agents. from the group consisting of risperidone (Risperdal(R) and 0112 The term “carrier defines a chemical compound ziprasidone (Geodon(R). In some embodiments, the salt of that facilitates the incorporation of a compound into cells or lithium is lithium carbonate. In some embodiments, the antip tissues. For example dimethyl sulfoxide (DMSO) is a com sychotic agent is selected from the group consisting of Arip monly utilized carrier as it facilitates the uptake of many iprazole (Abilify(R), EtrafonR), Droperidol (Inapsine(R). organic compounds into the ceils or tissues of an organism. Thioridazine (MellarilR). Thiothixene (Navane(R). Promet 0113. The term "diluent defines chemical compounds hazine (Phenergan.R.), Metoclopramide (ReglanR), Chlor diluted in water that will dissolve the compound of interest as prothixene (Taractan(R), Triavil(R), Molindone (Moban R), well as stabilize the biologically active form of the com Sertindol (Serlect R), Droperidol, Amisulpride (Solian(R), pound. Salts dissolved in buffered solutions are utilized as Melperone, Paliperidone (InvegaR), and Tetrabenzine. In diluents in the art. One commonly used buttered solution is Some embodiments, the antipsychotic is a D2 antagonist. In phosphate buttered saline because it mimics the salt condi Some embodiments, the antipsychotic is a typical antipsy tions of human blood. Since buffer salts can control the pH of chotic. In some embodiments, the antipsychotic is an atypical a solution at low concentrations, a buffered diluent rarely antipsychotic. modifies the biological activity of a compound. 0110. In one embodiment, the pimavanserin is co-admin 0114. The term “physiologically acceptable' defines a istered with the antipsychotic haloperidol. In another carrier or diluent that does not abrogate the biological activity embodiment, pimavanserin is co-administered with the antip and properties of the compound. sychotic risperidone. In various embodiments, the dose of 0115 Techniques for formulation and administration of haloperidol administered is less than about 0.5 mg, 1 mg, 2 the compositions described herein may be found in “Reming mg, or 3 mg per day. In various embodiments, the dose of ton's Pharmaceutical Sciences.” Mack Publishing Co., Eas risperidone administered is less than about 0.5 mg, 1 mg, 2 ton, Pa., 18th edition, 1990. mg, 3 mg, 4 mg, 5 mg, or 6 mg per day. In one embodiment, 0116 Suitable routes of administration may, for example, the dose of risperidone administered is about 2 mg per day. In include oral, rectal, transmucosal, topical, or intestinal various embodiments, the dose of pimavanserinadministered administration; parenteral delivery, including intramuscular, is from about 10 mg to about 15 mg, from about 15 mg to Subcutaneous, intravenous, intramedullary injections, as well about 20 mg, from about 20 mg to about 25 mg, from about 25 as intrathecal, direct intraventricular, intraperitoneal, intrana mg to about 30 mg, from about 30 mg to about 40 mg, from sal, or intraocular injections. The compounds can also be about 40 mg to about 50 mg, from about 50 mg to about 60 administered in Sustained or controlled release dosage forms, mg, from about 60 mg to about 70 mg, or from about 70 mg including depot injections, osmotic pumps, pills, transdermal to about 80 mg per day. In one embodiment, the dose of (including electrotransport) patches, and the like, for pro pimavanserin is about 20 mg per day. longed and/or timed, pulsed administration at a predeter 0111. Some embodiments include a pharmaceutical com mined rate. position comprising both a 5-HT2A inverse agonist or 0117 The pharmaceutical compositions of the present antagonist and the antipsychotic agent in a single dosage invention may be manufactured in a manner that is itself form. Such pharmaceutical compositions may comprise known, e.g., by means of conventional mixing, dissolving, physiologically acceptable Surface active agents, carriers, granulating, dragee-making, levigating, emulsifying, encap diluents, excipients, Smoothing agents, Suspension agents, Sulating, entrapping or tabletting processes. film forming Substances, and coating assistants, or a combi 0118 Pharmaceutical compositions for use as described nations thereof. Acceptable carriers or diluents for therapeu herein thus may be formulated in conventional manner using tic use are well known in the pharmaceutical art, and are one or more physiologically acceptable carriers comprising described, for example, in Remington's Pharmaceutical Sci excipients and auxiliaries which facilitate processing of the ences, 18th, Ed., Mack Publishing Co., Easton, Pa. (1990), active compounds into preparations which can be used phar which is incorporated herein by reference in its entirety. Pre maceutically. Properformulation is dependent upon the route servatives, stabilizers, dyes, Sweeteners, fragrances, flavoring of administration chosen. Any of the well-known techniques, agents, and the like may be provided in the pharmaceutical carriers, and excipients may be used as Suitable and as under composition. For example, sodium benzoate, ascorbic acid stood in the art; e.g., in Remington’s Pharmaceutical Sci and esters of p-hydroxybenzoic acid may be added as preser ences, above. Vatives. In addition, antioxidants and Suspending agents may 0119 Injectables can be prepared in conventional forms, be used. In various embodiments, alcohols, esters, Sulfated either as liquid solutions or Suspensions, Solid forms suitable US 2015/0231126 A1 Aug. 20, 2015 for solution or Suspension in liquid prior to injection, or as doses. For this purpose, concentrated Sugar Solutions may be emulsions. Suitable excipients are, for example, water, Saline, used, which may optionally contain gum arabic, talc, polyvi dextrose, mannitol, lactose, lecithin, albumin, sodium nyl pyrrolidone, carbopol gel polyethylene glycol, and/or glutamate, cysteinehydrochloride, and the like. In addition, if titanium dioxide, lacquer Solutions, and Suitable organic Sol desired, the injectable pharmaceutical compositions may vents or solvent mixtures. Dyesfuffs or pigments may be contain minor amounts of nontoxic auxiliary Substances, added to the tablets or dragee coatings for identification or to Such as wetting agents, pH buffering agents, and the like. characterize different combinations of active compound Physiologically compatible buffers include, but are not lim doses. ited to, Hanks’s solution, Ringer's Solution, or physiological I0123 Pharmaceutical preparations which can be used saline buffer. If desired, absorption enhancing preparations orally include push-fit capsules made of gelatin, as well as (for example, liposomes), may be utilized. Soft sealed capsules made of gelatin and a plasticizer, Such as 0120 For transmucosal administration, penetrants appro glycerol or Sorbitol. The push-fit capsules can contain the priate to the barrier to be permeated may be used in the active ingredients in admixture with filler Such as lactose, formulation. binders such as starches, and/or lubricants such as talc or 0121 Pharmaceutical formulations for parenteral admin magnesium Stearate and, optionally, stabilizers. In soft cap istration, e.g., by bolus injection or continuous infusion, Sules, the active compounds may be dissolved or Suspended in include aqueous solutions of the active compounds in water Suitable liquids, such as fatty oils, liquid paraffin, or liquid soluble form. Additionally, Suspensions of the active com polyethylene glycols. In addition, stabilizers may be added. pounds may be prepared as appropriate oily injection Suspen All formulations for oral administration should be in dosages sions. Suitable lipophilic solvents or vehicles include fatty Suitable for Such administration. oils such as sesame oil, or other organic oils such as Soybean, 0.124 For buccal administration, the compositions may grapefruit or almond oils, or synthetic fatty acid esters, such take the form of tablets or lozenges formulated in conven as ethyl oleate or triglycerides, or liposomes. Aqueous injec tional manner. tion Suspensions may contain Substances which increase the 0.125 For administration by inhalation, the compounds for Viscosity of the Suspension, Such as sodium carboxymethyl use according to the present invention are conveniently deliv cellulose, Sorbitol, or dextran. Optionally, the Suspension ered in the form of an aerosol spray presentation from pres may also contain Suitable stabilizers or agents that increase surized packs or a nebulizer, with the use of a suitable pro the solubility of the compounds to allow for the preparation of pellant, C.9. dichlorodifluoromethane, highly concentrated solutions. Formulations for injection trichlorofluoromethane, dichlorotetrafluoroethane, carbon may be presented in unit dosage form, e.g., in ampoules or in dioxide or other Suitable gas. In the case of a pressurized multi-dose containers, with an added preservative. The com aerosol the dosage unit may be determined by providing a positions may take such forms as Suspensions, solutions or valve to deliverametered amount. Capsules and cartridges of emulsions in oily or aqueous vehicles, and may contain for e.g., gelatin for use in an inhaler or insufflator may be formu mulatory agents such as Suspending, stabilizing and/or dis lated containing a powder mix of the compoundanda Suitable persing agents. Alternatively, the active ingredient may be in powder base such as lactose or starch. powder form for constitution with a suitable vehicle, e.g., 0.126 Further disclosed herein are various pharmaceutical sterile pyrogen-free water, before use. compositions well known in the pharmaceutical art for uses 0122 For oral administration, the compounds can be for that include intraocular, intranasal, and intraauricular deliv mulated readily by combining the active compounds with ery. Suitable penetrants for these uses are generally known in pharmaceutically acceptable carriers well known in the art. the art. Pharmaceutical compositions for intraocular delivery Such carriers enable the compounds of the invention to be include aqueous ophthalmic Solutions of the active com formulated as tablets, pills, dragees, capsules, liquids, gels, pounds in water-soluble form, Such as eyedrops, or in gellan syrups, slurries, Suspensions and the like, for oral ingestion by gum (Sheddan et al., Clin. Then, 23(3):440-50 (2001)) or a patient to be treated. Pharmaceutical preparations for oral hydrogels (Mayer et al. Ophthalmologica, 210(2):101-3 use can be obtained by combining the active compounds with (1996)); ophthalmic ointments; ophthalmic suspensions, Solid excipient, optionally grinding a resulting mixture, and Such as microparticulates, drug-containing Small polymeric processing the mixture of granules, after adding Suitableaux particles that are suspended in a liquid carrier medium (Joshi, iliaries, if desired, to obtain tablets or dragee cores. Suitable A. J. Ocul. Pharmacol., 10(1):29-45 (1994)), lipid-soluble excipients are, in particular, fillers such as Sugars, including formulations (Alm et al., Prog. Clin. Biol. Res., 312:447-58 lactose, Sucrose, mannitol, or Sorbitol, cellulose preparations (1989)), and microspheres (Mordenti, Toxicol. Sci., 52(1): Such as, for example, maize starch, wheat starch, rice starch, 101-6 (1999)), and ocular inserts. All of the above-mentioned potato starch, gelatin, gum tragacanth, methyl cellulose, references, are incorporated herein by reference in their hydroxypropymethyl-cellulose, sodium carboxymethylcel entireties. Such suitable pharmaceutical formulations are lulose, and/or polyvinylpyrrolidone (PVP). If desired, disin most often and preferably formulated to be sterile, isotonic tegrating agents may be added. Such as the cross-linked poly and buffered for stability and comfort. Pharmaceutical com vinyl pyrrolidone, agar, oralginic acid or a salt thereof such as positions for intranasal delivery may also include drops and Sodium alginate. Dragee cores are provided with Suitable sprays often prepared to simulate in many respects nasal coatings. For this purpose, concentrated Sugar Solutions may secretions to ensure maintenance of normal ciliary action. As be used, which may optionally contain gum arable, talc, poly disclosed in Remington's Pharmaceutical Sciences, 18th Ed., vinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or Mack Publishing Co., Easton, Pa. (1990), which is incorpo titanium dioxide, lacquer Solutions, and Suitable organic Sol rated herein by reference in its entirety, and well-known to vents or solvent mixtures. Dyestuffs or pigments may be those skilled in the art, suitable formulations are most often added to the tablets or dragee coatings for identification or to and preferably isotonic, slightly buffered to maintain a pH of characterize different combinations of active compound 5.5 to 6.5, and most often and preferably include antimicro US 2015/0231126 A1 Aug. 20, 2015

bial preservatives and appropriate drug stabilizers. Pharma 0.132. In some embodiments, the 5-HT2A inverse agonist ceutical formulations for intraauricular delivery include Sus or antagonist is long acting while the co-administered antip pensions and ointments for topical application in the ear. sychotic is short acting. The long acting or short acting prop Common solvents for Such aural formulations include glyc erties may be due to long and short half lives, respectively. erin and water. Marty antipsychotics have relatively short occupancy times at 0127. The compounds may also be formulated in rectal D2 receptors. If a similarly short acting 5-HT2A inverse compositions such as Suppositories or retention enemas, e.g., agonist or antagonist were used in combination with Such containing conventional Suppository bases such as cocoa but antipsychotics, then the modulating effect of the 5-HT2A ter or other glycerides. inverse agonist or antagonist on D2 activity would be dimin 0128. In addition to the formulations described previously, ished at the same time that. D2 receptor occupancy is low, the compounds may also be formulated as a depot prepara potentially resulting in a loss of efficacy, a problem that is tion. Such long acting formulations may be administered by compounded if a low dose of antipsychotic is used. In con implantation (for example Subcutaneously or intramuscu trast, while not being bound by any particular theory, if a larly) or by intramuscular injection. Thus, for example, the 5-HT2A inverse agonist orantagonist that has relatively long compounds may be formulated with Suitable polymeric or receptor occupancy compared to the antipsychotic is used, hydrophobic materials (for example, as an emulsion in an then high 5-HT2A receptor occupancy and resulting D2 acceptable oil) or ion exchange resins, or as sparingly soluble modulating effect is maintained during the periods when the derivatives, for example, as a sparingly soluble salt. D2 receptor occupancy is at its lowest. 0129. For hydrophobic compounds, a suitable pharmaceu I0133. The benefits of combining a longer acting drug that tical carrier may be a cosolvent system comprising benzyl improves the therapeutic window of a shorter acting thera alcohol, a nonpolar Surfactant, a water-miscible organic poly peutic agent is also applicable to combinations other than mer, and an aqueous phase. A common cosolvent system used 5-HT2A inverse agonists or antagonists with D2 antagonists. is the VPD co-solvent system, which is a solution of 3% w/v. For example, while not being bound by any particular theory, benzyl alcohol, 8% w/v of the nonpolar surfactant Polysor it is believed that the efficacy of many drugs is limited to a bate 80TM, and 65% w/v polyethylene glycol 300, made up to range of drug levels (therapeutic window). FIG. 1A is an volume in absolute ethanol. Naturally, the proportions of a illustrative graph of the drug level upon sequential adminis co-solvent system may be varied considerably without tration of a single drug. The therapeutic window (shown as destroying its solubility and toxicity characteristics. Further the shaded region on the graph) is bounded on the lower side more, the identity of the co-solvent components may be var by the minimum level of the drug that must be present to ied, for example, other low-toxicity nonpolar Surfactants may achieve a therapeutic benefit and on the higher side by the be used instead of POLYSORBATE 80TM, the fraction size of level of the drug such that the toxicity would outweigh any polyethylene glycol may be varied; other biocompatible therapeutic benefit above this plasma concentration of the polymers may replace polyethylene glycol, e.g., glycol poly drug. As illustrated for some drugs with a narrow therapeutic vinyl pyrrolidone; and other Sugars or polysaccharides may window, even the optimal dose results in plasma levels out substitute for dextrose. side both the upper and lower bounds of the therapeutic 0130. Alternatively, other delivery systems for hydropho window (the drug has toxicity limited efficacy). That is, while bic pharmaceutical compounds may be employed. Lipo not being bound to any particular theory, it is believed that Somes and emulsions are well known examples of delivery because the drug causes toxicity when the drug level reaches vehicles or carriers for hydrophobic drugs. Certain organic a particular concentration, the maximum dosage that can be Solvents such as dimethylsulfoxide also may be employed, administered is limited. Thus, during a period of Successive although usually at the cost of greater toxicity. Additionally, dosings of a drug administered alone with a given half-life, the compounds may be delivered using a Sustained-release the level of the drug can cycle in and out of the therapeutic system, Such as semipermeable matrices of Solid hydropho window such that between doses, the drug levels can fall bic polymers containing the therapeutic agent. Various Sus below those levels required for efficacy of the drug. tained-release materials have been established and are well I0134. While not being bound to any particular theory, it is known by those skilled in the art. Sustained-release capsules believed that a secondary drug that, by lowering the plasma may, depending on their chemical nature, release the com level associated with efficacy, can increase the therapeutic pounds for a few weeks up to over 100 days. Depending on the window for the primary drug. However, if the half life of the chemical nature and the biological stability of the therapeutic secondary drug is short, then the beneficial effects on the reagent, additional strategies for protein stabilization may be therapeutic window will be transient and will be absent at the employed. time when the drug levels of the primary agent are lowest. 0131 Agents intended to be administered intracellularly Thus the beneficial effects of the modulatory agent may not may be administered using techniques well known to those of be apparent. FIG. 1B illustrates the widening of the therapeu ordinary skill in the art. For example, Such agents may be tic window in the case where the primary and secondary drugs encapsulated into liposomes. All molecules present in an have similar half-lives. Only the drug level of the primary aqueous solution at the time of liposome formation are incor drug is depicted. FIG. 1B illustrates that, although the size of porated into the aqueous interior. The liposomal contents are the therapeutic window is increased, the time that the primary both protected from the external micro-environment and, drug is within the therapeutic window is not significantly because liposomes fuse with cell membranes, are efficiently increased compared to the primary drug administered alone delivered into the cell cytoplasm. The liposome may be (see FIG. 1A). For example, if the primary drug is a D2 coated with a tissue-specific antibody. The liposomes will be and the secondary drug is a 5-HT2A targeted to and taken up selectively by the desired organ. inverse agonist or antagonist, it is believed that the 5-HT2A Alternatively, Small hydrophobic organic molecules may be antagonist or inverse agonist would increase the therapeutic directly administered intracellularly. window for the D2 antagonist when the level of the secondary US 2015/0231126 A1 Aug. 20, 2015 drug exceeds its own required level of efficacy. While the sis was conducted. Subjects with a DSM-IV diagnosis of secondary drug lowers the required level of the primary drug, Schizophrenia and a baseline score on the Positive and Nega it does So when the levels of the primary drug are already high. tive Syndrome Scale (PANSS) of at least 65 (high level of Consequently, it is believed that the fraction of time in which psychopathology), and a score of 4 or higher on two items of there is efficacious therapy may not be increased through this the psychosis subscale were enrolled. Subjects were ran approach. domly assigned to be administered haloperidol 2 mg per day 0135 While not being bound to any particular theory, it is co-administered with placebo, haloperidol 2 mg per day co believed that when a secondary drug has a longer half-life administered with pimavanserin at 20 mg per day, 2 mg than the primary drug, the enhanced therapeutic window can risperidone per day co-administered with a placebo, 2 mg be maintained into the next dose. FIG. 1C depicts the result risperidone per day co-administered with 20 mg of pimavan ing Sustained increase in the therapeutic window. Because the serin, or 6 mg risperidone per day co-administered with pla secondary drug is present at high levels throughout each cebo. Subjects administered 2 mg of risperidone per day dosing period of the primary drug, the lower limit of the received two doses of 1 mg each. Subjects administered 6 mg therapeutic window stays consistently low. Thus, the primary of risperidone per day received two doses of 3 mg each. This drug is always within the therapeutic window, thereby dra study lasted approximately nine weeks and included a screen matically increasing the fraction of time in which there is ing period to allow for wash out of prior antipsychotics (2 to efficacious therapy. Implicit in this is the opportunity to lower 14 days) followed by six weeks of active fixed dosing. Sub the dose of the primary drug to a level that diminishes its toxic jects were returned to the clinic two weeks later for a follow effects while maintaining its efficacy. up visit. Subjects were treated as in-patients during screening 0136. Accordingly, some embodiments include adminis and for the first 14 days of the trial and thereafter, at the tering a first agent in combination with a second agent where discretion of each principal investigator (PI), completed the the first agent has a higher half-life than the second agent. In trial as outpatients. Subjects were evaluated at Screening, some embodiments, the half-life of the first agent is at least after a drug-free lead-in period (Baseline Day -1), and peri about 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, odically thereafter by the PANSS the Clinical Global Impres 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, or sion Scale-Severity (CGI-S), the Calgary Depression Scale more than 4.0 times higher than the half-life of the second for Schizophrenia (CDSS), the Simpson and Angus Scale agent. In some embodiments, the first agent modulates the (SAS), and the Barnes Akathisia Scale (BAS). activity of the second agent. In some embodiments, the first 0140 Male and female subjects, age inclusive from 18-65, and second agents are selected Such that their relative half with a clinical diagnosis of schizophrenia (DSM-IV 295. lives and the modulating effect of the first agent on the second XX), are enrolled. Subjects are experiencing an acute psy agent results in the second agent being present at an effica chotic exacerbation, and have at least a moderate degree of cious dose during at least about 50%, 60%, 70%, 80%, 90%, psychopathology (total score on the PANSS of 65 or greater), or 100% of the time between successive dosing of the second and a score greater than or equal to 4 on two of the four agent. following PANSS items: delusions, hallucinatory behavior, 0.137 Some embodiments include selecting appropriate conceptual disorganization or Suspiciousness, where at least pharmaceutical agents to achieve the results indicated above. one of the two items must be delusions or hallucinatory Some such embodiments include determining whether a first behavior. Subjects have a history of a previous psychotic pharmaceutical agent modulates a pharmacological property exacerbation with a positive response to antipsychotic ofa second pharmaceutical agent, Such as by invitro assays or therapy, and a history of at least 3 months of prior antipsy in vivo measurements. In one embodiment, the pharmaco chotic therapy. In other words, subjects who have a history of logical property that is modulated is a receptor occupancy. being refractory to antipsychotic therapies, or are experienc For example, the first pharmaceutical agent may decrease or ing their first episode of psychosis, are excluded. increase the occupancy of a particular receptor. In one 0141 All subjects received twice daily (BID) oral doses of embodiment, the pharmacological property is the minimum study medication. Subjects receiving haloperidol received a dose at which the second pharmaceutical agent has an effica total of 2 mg per day in a singleam dose followed by a placebo cious effect. For example, the first pharmaceutical agent may pm dose. Subjects administered 2 mg of risperidone per day decrease the minimum efficacious dose of the second phar received two doses of 1 mg each. Subjects administered 6 mg maceutical agent. Some embodiments further include deter of risperidone per day received two doses of 3 mg each. mining whether the first pharmaceutical agent has a longer Subjects administered pimavanserin received a total of 20 mg half-life than a second pharmaceutical agent. per day in a single am dose followed by a placebo pm dose. 0.138. In some embodiments, the first agent has D2 antago Thus each subject received BID dosing of study nist activity (e.g., haloperidol or risperidone. In some in a blinded manner. embodiments, the second agent is a 5-HT2A inverse agonist orantagonist. For example, in Some embodiments, the second 0142. Subjects were evaluated at baseline/enrollment agent is pimavanserin or any of the 5-HT2A inverse agonists (Study Day -1), and periodically thereafter throughout the or antagonists described herein. active dosing portion of the trial (Study Days 1, 8, 15, 22, 29. 36, and 43). These clinical evaluations included vital signs, EXAMPLES medical history and exam (including psychiatric and brief neurological evaluation). ECG measurements, the adminis Example 1 tration of clinical rating scales, safety evaluations including reported or observed adverse events, clinical chemistries (ex Haloperidol and Risperidone Combinations cept Days 1, 22 and 36), and plasma sampling for the pima Administered to Schizophrenic Patients Vanserin, haloperidol, and risperidone concentrations. A dual 0.139. A randomized, double blind, multi-center study of follow-up visit on Day 57, two weeks after the termination of Schizophrenic Subjects with an acute exacerbation of psycho the active dosing portion of the trial, included a medical US 2015/0231126 A1 Aug. 20, 2015 evaluation, safety clinical labs, and plasma sampling for greater than or equal to 20% improvement In PANSS total at pimavanserin, haloperidol, and risperidone concentrations. Day 15. FIG.3B shows the same data at Day 43. The response Prolactin levels, weight gain, and glucose levels were also to the pimavanserin/risperidone was significantly greater monitored. than low dose (2 mg) and high dose (6 mg) risperidone at Day 0143. The clinical rating scale for psychosis and negative 15 (p=0.002 and 0.013, respectively), and significantly symptoms is the Positive and Negative Symptom Scale greater than low dose risperidone at Day 43 (p=0.001). (PANSS). The Clinical Global Impression Scale (CGI-S) is a 0151 FIG. 4A is a graph depicting the change from base global assessment of clinical severity. Scales for extrapyra line (mean+SE) in the PANSS positive symptom scale. The midal symptoms (EPS) include the Simpson and Angus Scale response to the pimavanserin/risperidone combination was (SAS) and the Barnes Akathisia Scale (BAS). Finally, the significantly greater than low dose risperidone at Days 15-36 Calgary Depression Scale for Schizophrenia (CDSS) was (p<0.05). The combination was not significantly different included. from high dose risperidone. FIG. 4B shows the change in the 0144. The PANSS is a 30-item, 7-point rating system that PANSS negative symptom scale. The response to the pima was adapted from the Brief Psychiatric Rating Scale. It has Vanserin/risperidone combination was significantly greater sections that specifically measure positive symptoms, nega than low dose risperidone at Day 15 and later (p<0.05). The tive symptoms, and general psychopathology in Schizo combination was not significantly different from high dose phrenic subjects. The PANSS is widely used in trials of antip risperidone. sychotic ding treatment, and has been formally validated for 0152 FIG. 5A is a graph depicting the change from base Such use. The entire scale was administered at Screening at line (mean+SE) in the PANSS general psychopathology baseline (Study Day -1), and during each clinical evaluation scale. The response to the pimavanserin/risperidone combi except for Study Day 1 and Day 57. nation was significantly greater than low dose risperidone for (0145 The CGI-S consists of three subscales The CGI-S all time points from Day 15 on (p<0.005). The combination (severity of illness) has been designed to evaluate global also showed trends for greater change compared to high dose severity of illness. The CGI-S was administered at baseline risperidone at Days 15 and 20. FIG. 5B shows the change in (Study Day -1), and at each clinical evaluation, except for the PANSS cognition scale. The response for the pimavan Study Days 1 and 57. serin/risperidone combination was significantly better than 0146 The SAS is an extrapyramidal motor effect measure. low dose risperidone at Day 36 (p<0.05) and trends for supe This 10-item, 5-point Scale is designed to assess a range of riority at Days 22 (p<0.05) and 43 (p<0.07). extrapyramidal symptoms including disturbances in gait, 0153 FIG. 6 is a graph depicting the change from baseline muscle tone, and tremor. This scale was administered at base (meant-SE) for the CGI-seventy scale. The change for the line (Study Day -1), and at all clinical evaluations, except for pimavanserin/risperidone combination was significantly dif Study Day 57. ferent from low dose risperidone from Day 15-43. No signifi 0147 The BAS is another extrapyramidal motor effect cant difference was observed between the combination and measure. The BAS was designed to measure drug-induced high dose risperidone. akathisia that occurs specifically with use of antipsychotic 0154 FIG. 7A is a bar graph depicting the percent of agents. The BAS is a four-item fully anchored scale. Three subjects with a weight gain of at least 7% at the end of the items (i.e., objective akathisia, Subjective awareness of rest study. The results indicate that fewer patients experienced lessness, and Subjective distress related to restlessness) are clinically significant weight gain when receiving the pima rated on a 4-point Scale, and the global clinical assessment of Vanserin/risperidone combination as compared to patients akathisia uses a 6-point Scale. This scale was administered at receiving either low dose (p=0.08) or high dose (p=0.031) or baseline (Study Day -1), and at all clinical evaluations, risperidone alone. FIG. 7B is a bar graph depicting mean except for Study Day 57. weight gain at the end of the study compared to baseline. 0148. The effect of adjunctive pimavanserin treatment on Patients receiving a pimavanserin/risperidone combination affective symptoms was also assessed. The CDSS is a 9-item, had less weight gain than high dose risperidone (p=0.05). 4-point Scale that was specifically designed to measure 0155 FIGS. 8A and 8B are graphs depicting the change depressive symptoms in psychotic Subjects, separate from the from baseline (meant-SE; ng/mL) of prolactin levels at the positive, negative, and extrapyramidal symptoms observed in end of treatment for males and females, respectively. The this population. It has been widely used in treatment trials in prolactin levels in both males and females were significantly schizophrenia and has been validated for such use. This scale less for the pimavanserin/risperidone combination patients was administered at Screening and at all clinical evaluations, than for those receiving high dose risperidone (p=0.015 for except for Study Days 1 and 57. males, p=0.004 for females). 0149. During the screening period (from screening to 0156 FIG. 9 is a bar graph indicating the changes in glu Study Day -1), all subjects receive only permitted concomi cose levels from baseline. The results indicated that patients tant medication as deemed necessary. All prior antipsychotic, receiving the pimavanserin/risperidone combination had less mood stabilization and antidepressant therapy are completely of an increase in glucose than those receiving high dose washed out at least two days prior to randomization (Day -1). risperidone (p=0.024). Thereafter, all investigational study drugs are administered 0157. This results of the study demonstrate that co-admin twice a day for the duration of the trial. istering pimavanserin with haloperidol provided highly sig 0150 FIG. 2 is a graph depicting the total change nificant antipsychotic efficacy (p<0.0001) with similar effi (meaniSE) from baseline in the PANSS score for each treat cacy to haloperidol administered alone. FIG. 10 is a graph ment group. The pimavanserin/risperidone combination pro depicting the percent of responders, defined as those Subjects duced a significantly greater decrease in PAKSS score start experiencing at least a 20% reduction in PANSS score. The ing at Day 15 as compared to low dose risperidone (2 mg). results indicate that the combination treatment trended FIG. 3A is a bar graph depleting the percent of subjects with toward a faster onset of efficacy. Specifically, at two weeks US 2015/0231126 A1 Aug. 20, 2015

after the start of treatment, the percent responders for the (0163 The conclusions are summarized as follows: haloperidol/pimavanserin combination were higher than for 0.164 Pimavanserin potentiated efficacy of low dose haloperidol alone. risperidone on psychopathology while reducing side 0158. As Table 1 demonstrates, the haloperidol/pimavan effects. serin combination also resulted in less weight gain than 0.165 Pimavanserin did not potentiate the efficacy of observed when administering haloperidol alone. haloperidol. 0166 Low dose risperidone was significantly less effec TABLE 1. tive than the other treatments. 0.167 Pimavanserin enhanced the efficacy of low dose Haloperidol Haloperidol + Pimavanserin risperidone at all time points from week 2 on with regard Initial mean weight (kg) 82.993 82.943 to PANSS Total, POS, NEG, General, and CGI. Final mean weight (kg) 83.759 83.385 0168 Pimavanserin/risperidone was more effective Mean weight gain (kg) 0.7657 O.4426 than high dose risperidone and low dose risperidone at day 15 with regard to % patients with >20% decrease in 0159. Co-administering pimavanserin with risperidone PANNS Total. also provided highly significant antipsychotic efficacy (p<0. 0.169 Pimavanserin/risperidone was as effective as 0001). Efficacy enhancement was observed when compared high dose risperidone, haloperidol and pimavanserin/ to 2 mg of risperidone administered alone (mean change in haloperidol at all time points, with all measures. PANNS score of 23.0 vs. 16.6 points) and similar efficacy was 0170 Pimavanserin/risperidone had less % of patients observed when compared to 6 mg of risperidone administered with >7% weight gain than high dose risperidone or low alone. Efficacy of the combination was observed for both dose risperidone. positive and negative symptoms of psychosis. The co-admin 0171 Serum glucose and prolactin levels (PRL) were istration resulted in improved treatment of emotional with lower in pimavanserin/risperidone than high dose risperi drawal, lack of spontaneity and flow of conversation, abnor done, PRL levels were lower in haloperidol-treated patients mal mannerisms and posturing, motor retardation, compared to risperidone patients. uncooperativeness, lack of judgment and insight, poor 0.172. There was a trend to less akathesia in the pima impulse control, and preoccupation as compared to 6 mg per Vanserin co-therapy groups compared to the respective day of risperidone administered alone. risperidone and haloperidol arms. 0160 FIG. 11 is a graph depicting the percent of respond Example 2 ers for those Subjects receiving risperidone, defined as those subjects experiencing at least a 20% reduction in PANSS Combinations of Haloperidol and Risperidone with score. The results indicate that the combination treatment Pimavanserin for Suppressing Drug-Induced resulted in a faster onset of efficacy. Specifically, at two weeks Hyperactivity in Mice after the start of treatment, the percent responders for the risperidone/pimavanserin combination were higher than for 0173 Male non-Swiss albino (NSA) mice and Sprague risperidone alone (both the 2 mg and 6 mg doses). Dawley (SD) rats (Harlan, San Diego, Calif.) served as sub jects for the present investigation. Animals were housed in 0161. As Table 2 demonstrates, the risperidone/pimavan climate-controlled rooms on a 12/12 light dark cycle with on serin combination resulted in less weight gain than observed lights at 0600 hr. Rats were housed in groups of two and mice when administering 6 mg of risperidone alone. The difference were housed in groups of eight. Food and water was available was approaching statistical significance (p=0.0784). ad libitum except during experimental procedures. At the time of testing, mice weighed 20-30 g and the rats weighed TABLE 2 between 275-325 g. 2 mg 6 mg Risperidone + 0.174 Amphetamine, dizocilpine (i.e., MK-801), and Risperidone Risperidone pimavanserin haloperidol were obtained from Sigma (St. Louis, Mo.). Ris Initial mean weight (kg) 80.702 79.216 79.533 peridone was obtained from Toronto Research Chemicals Final mean weight (kg) 81.856 81.332 80.6OO (North York, ON, Canada). Pimavanserin were synthesized Mean weight gain (kg) 1.1540 2.1162 1.0667 by ACADIA Pharmaceuticals, Inc. Drugs were administered eitherina volume of 0.1 mL per 10g body weight or of 1.0 mL per kg body weight to mice and rats, respectively. The vehicle used for amphetamine, dizocilpine, and ACP-103 was saline. Conclusion Amphetamine and dizocilpine were administered intraperi toneally (ip). The vehicle used for haloperidol and risperi 0162 The combination of low dose risperidone with pimavanserin was Superior to that of either low dose or high done was 10% Tween 80 in saline unless otherwise specified. dose risperidone alone in terms of time of onset of response Haloperidol and risperidone were administered subcutane and percent of patients with good clinical response. The effi ously (Sc), unless otherwise noted. The doses of pimavanserin cacy of haloperidol was not potentiated by pimavanserin, are expressed as free-base and were administered by the sc perhaps because with haloperidol alone, the occupancy of D2 rOute. receptors is sufficient to achieve optimal outcome, whereas Amphetamine-Induced Hyperlocomotor Activity that of low dose risperidone alone is not. The advantage of Assay using low doses of atypicals +pimavanserin extends to reduced side effect burden on metabolic measures and EPS 0.175 Hyperlocomotion was produced in mice by admin and, potentially, to a broadened efficacy. istration of amphetamine (3 mg/kg) 15 min prior to entering US 2015/0231126 A1 Aug. 20, 2015

motor activity chambers (AccuScan Instruments, Columbus, squares), demonstrated an enhanced suppression of amphet Ohio). Dose response curves were constructed for haloperi amine-induced hyperlocomotor activity. dol in the presence of vehicle or a fixed dose of pimavanserin 0180. The raw data contained in FIG. 12A were converted (0.03 mg/kg). Vehicle or haloperidol was injected 30 min to % MPI to generate dose-response curves depicted in FIG. prior to entering activity chambers. Vehicle or pimavanserin 12B. Haloperidol (open squares) produced a dose-dependent was given 30 min prior to haloperidol (i.e., 60 min prior to attenuation of hyperactivity elicited by amphetamine with a entering activity chambers), immediately prior to placing the calculated IDs value of 0.012 mg/kg (0.009-0.016; 95% CI). mice into the activity chambers, the presence of ataxia and However, when combine with a fixed dose of pimavanserin muscle incoordination was determined using the horizontal (0.03 mg/kg, filled squares), the dose-response curve for wire test (Vanover et al., 2004). Once inside the chambers, haloperidol was significantly shifted to the left by a factor of total distance traveled (DT) in cm was determined across a 15 approximately 10 with a calculated IDs value of 0.0013 min session. In order to generate dose-response curves, raw mg/kg (0.0005-0.0031: 95% CI). The combination of pima DT data were converted to % MPI:% MPI-((DT drug or drug vanserin and haloperidol resulted in a 9.5-fold (3.8-23.8; 95% combination-DT amphetamine control)/DT vehicle control CI) shift in potency. Each data point represents a minimum n DT amphetamine control))* 100. The IDs values and the of 8. corresponding 95% CI were determined as previously men tioned. Mice bad no prior exposure to the chambers and each Effects of Haloperidol and Pimavanserin, Alone and dose combination was tested in separate groups of mice. in Combination, on Suppression of Dizocilpine-Induced Hyperlocomotion in Mice Dizocilpine-Induced Hyperlocomotor Activity Assay 0181 FIG. 13A is a graph depicting dose response curves 0176 Hyperlocomotion was produced in mice by admin for haloperidol (open squares), pimavanserin (filled squares), istration of dizocilpine (0.3 mg/kg) 15 min prior to entering and the combination of haloperidol with pimavanserin in a motor activity chambers. Dose response curves were con 1:1 feed dose ratio (filled circles) on the suppression of dizo structed for haloperidol, risperidone and pimavanserin. Halo cilpine-induced hyperactivity. Each data point represents a peridol or risperidone was injected 30 min prior to, and pima minimum n of 16. As expected, dizocilpine treatment signifi Vanserin was administered 60 min prior to entering the cantly increased DT to 2227+116 cm from 792+40 cm activity chambers. Immediately prior to placing the mice into obtained in the vehicle controls. Administration of either the activity chambers the presence of ataxia and muscle inco haloperidol or pimavanserin elicited a dose-dependent ordination was determined as previously described and DT attenuation of dizocilpine-induced hyperlocomotion achiev was determined across a 15 min session. Raw data were ing IDs values of 0.07 mg/kg (0.063-0.087; 95% CI) and transformed to % MPI and IDso values and corresponding 0.09 mg/kg (0.067-0.12: 95% CI), respectively. Given that 95% CI were determined as previously described. Mice had haloperidol and pimavanserin were equipotent in this assay, a no prior exposure to the chambers and each dose combination 1:1 fixed-dose ratio (haloperidol:ACP-103) was administered was tested in separate groups of mice. in fractions of the approximated IDso dose combinations of (0177. Drug-Interaction Studies 0.06+0.06 mg/kg (IDs/2=0.03+0.03 mg/kg. IDs/4-0.015+ 0.178 Isobolographic analysis was used to determine the 0.015 mg/kg. IDs/8-0.0075+0.0075 mg/kg). Co-adminis nature of the drug interaction between either haloperidol or tration of haloperidol and pimavanserin produced a dose risperidone and pimavanserin on Suppression of dizocilpine dependent attenuation of hyperlocomotor activity induced by induced hyperlocomotor activity. This method is based on the dizocilpine achieving a % MPI of 103+6%. comparison of dose combinations in which the doses of each 0182 Isobolographic analysis conducted using the individual agent are determined to be equi-efficacious. In this omnipotent ratio and the resulting isobologram is presented case, dose-response curves were generated following co-ad in FIG. 13B. The calculated IDs (and 95% CI) values for ministration of either haloperidol or risperidone with pima pimavanserin and haloperidol when administered alone Vanserin in a fixed dose ratio based on the individual calcu (open Squares) are plotted on the X- and y-axes, respectively. lated IDso values. Therefore, separate groups received: The dashed line connecting these two points represents the pimavanserin IDso-haloperidol or risperidone (pimavan line of theoretical additivity. The experimental IDs (filled serin-i-haloperidol or pimavanserin-risperidone), IDso value circle, B) for the dose combination was significantly less than and 95% CI for each drug combination was obtained. the theoretical IDs (filled square, A), indicating a synergistic interaction. The experimental IDso for the dose mixture was Effects of Haloperidol Alone, and in Combination significantly less than the theoretical IDs, values of 0.04 with Pimavanserin, on Suppression of mg/kg (0.03-0.05: 95% CI) and 0.08 mg/kg (0.68-0.93; 95% Amphetamine-Induced Hyperlocomotion in Mice CI), respectively. These results indicate that efficacy is main tained at 50% of haloperidol dose. 0179 FIG. 12A is a graph illustrating the distance traveled as a function of haloperidol dose for the various administered Effects of Risperidone and Pimavanserin, Alone and agents. Relative to vehicle controls (open circle), amphet in Combination, on Suppression of amine (open triangle) significantly increases hyperlocomotor Dizocilpine-Induced Hyperlocomotion in Mice activity in mice (increased DT to 2764+230 cm from 876+42 cm obtained in the vehicle controls). Pimavanserin at a dose 0183 FIG. 14A is a graph depicting dose response curves of 0.03 mg/kg (filled circle) failed to suppress hyperlocomo for risperidone (open squares), pimavanserin (filled squares), tion produced by amphetamine. In contrast, haloperidol and the combination of risperidone with pimavanserin in a (open Squares) dose dependently attenuated hyperactivity 1:18 fixed dose ratio (filled circles) on the suppression of produced by amphetamine. However, haloperidol when com dizocilpine-induced hyperactivity. Each data point represents bined with a fixed dose of pimavanserin (0.03 mg/kg, filled a minimum n of 16. As in the previous experiment, dizo US 2015/0231126 A1 Aug. 20, 2015

cilpine treatment significantly increased total DT to 0186 The mechanism by which 5-HT, receptor blockade 2020+223 cm from 649-67 cm obtained in the vehicle con enhances the action orantipsychotics (APDs) in these models trols. Administration of either risperidone or pimavanserin is unknown, however, microdialysis and other studies Suggest elicited a dose-dependent attenuation of dizocilpine-induced several possibilities. While not being bound by any particular hyperlocomotion achieving IDso values of 0.0045 mg/kg theory, one possibility is that 5-HT, inverse agonists may (0.003-0.006: 95% CI) and 0.09 mg/kg (0.067-0.12; 95% CI), have regionally specific effects on dopamine (DA) transmis respectively. Given that risperidone was more potent than sion. Previous studies have shown that DOI increases DA pimavanserin in this assay, a 1:18 fixed-dose ratio (risperi release and potentiates amphetamine-induced DA release in done:pimavanserin) was administered in fractions of the the nuclear accumbens (NAC), suggesting that 5-HT, recep approximated IDso dose combinations of 0.005+0.09 mg/kg tor inverse agonists are more apt to modulate evoked, rather (IDs/2=0.0025+0.045 mg/kg. IDs/4=0.00125+0.0225 than basal, DA release. Haloperidol, which potently inhibits mg/kg: IDs/8=0.000625+0.01 125 mg/kg). Co-administra amphetamine hyperactivity, has been shown to paradoxically tion of risperidone and pimavanserin produced a dose-depen increase DA release in the NAC, an effect blocked by pima dent attenuation of hyperlocomotor activity induced by dizo Vanserin. These data Suggest that pimavanserin may potenti cilpine achieving a % MPI of 82+8%. ate the actions of haloperidol via director indirect modulation 0184 Isobolographic analysis was conducted using the of evoked DA release in the NAC. Another possibility is that fixed dosing ratio and the resulting isobologram is presented 5-HT, inverse agonists may block a "pro-psychotic drive in FIG. 14. The calculated IDs (and 95% CI) values for associated with APD-induced enhanced serotonergic trans pimavanserin and risperidone when administered alone (open mission in limbic or cortical structures. Following systemic squares) are plotted on the X- and y-axes, respectively. The administration of NMDA antagonists, extracellular DA and dashed line connecting these two points represents the line of 5-HT concentrations rise in the NAC, and medial prefrontal theoretical additivity. The experimental IDs (filled circle, B) cortex (mPFC). High closes of atypical APDs, such as cloza for the dose combination was significantly less than the theo pine and olanzapine, but not typical APDs, such as haloperi retical IDs (filled square. A), indicating a synergistic inter dol, produce preferential increases in DA release in the mPFC action. The experimental IDso for the dose mixture was sig compared to the NAC, a property that may explain how atypi nificantly less than the theoretical IDs, values of 0.0032 cal APDS improve cognition in Schizophrenia. Regardless of mg/kg (0.0007-0.005895% CI) and of 0.045 mg/kg (0.035 the mechanism, these findings indicate that pimavanserin has 0.054: 95% CI), respectively. These results indicate that effi dose-sparing actions for APDS in models predictive of antip cacy is maintained at /3 of risperidone dose. sychotic action. 0187. In conclusion, the above data suggests that pima Conclusion Vanserin, via 5-HT2 receptor antagonism or inverse ago nism, results in a significant dose-sparing effect Such that 0185. Pimavanserin, at a dose that does not suppress antipsychotic efficacy can be maintained, or improved, while amphetamine-induced hyperactivity, when combined with concomitantly reducing the severity of unwanted side effects haloperidol, produced an approximate 10-fold shift in the mediated via D receptor antagonism. The findings with ris potency of haloperidol against amphetamine-induced hyper peridone Suggest that the dose-sparing benefits of pimavan activity. Further, pimavanserin interacted synergistically with serin will be manifested even with those atypical APDs hav haloperidol, and with risperidone, to reduce dizocilpine-in ing an inherently high affinity for 5-TH receptors. This is duced hyperactivity. The Supra-additive actions of pimavan consistent with clinical findings indicating that even for those serin were not achieved by simply altering the pharmacoki APDs which have relatively high affinity for 5-HT, recep netics of either haloperidol or risperidone, as brain exposures tors, 5-HT, receptor blockade is not fully achieved at clini for these agents were not significantly altered in the presence cally tolerated doses. of pimavanserin. For example, Table 3 indicates brain levels of pimavanserin and haloperidol for various dosages. The Example 3 results indicate that full efficacy can be achieved using the combination with one half haloperidol brain concentration. Combinations of Aripiprazole and Quetiapine with The doses used in these studies are consistent with a 5-HT, Pimavanserin for Suppressing Drug-Induced receptor mechanism of action. These data indicate that even Hyperactivity in Mice for compounds that possess high affinity for 5-HT, recep 0188 The protocol described above in Example 2 was tors, complete 5-HT2 receptor occupancy is not likely repeated using aripiprazole and quetiapine antipsychotics. achieved at doses that elicit antipsychotic-like activity. FIG. 15A is graph illustrating the distance traveled as a func tion of aripiprazole dose for the various administered agents. TABLE 3 Relative to vehicle controls (open circle), amphetamine (open Treatment Pimavanserin brain levels Haloperidol brain levels triangle) significantly increases hyperlocomotor activity in conditions (nmol/kg) (nmol/kg) mice. Pimavanserin at a dose of 0.03 mg/kg (filled circle) failed to suppress hyperlocomotion produced by amphet Pim + Veh 23 (+6) Veh + Hal (0.003) <10 amine. In contrast, aripipraxole (open squares) dose depen Veh + Hal (0.01) 43 (+5) dently attenuated hyperactivity produced by amphetamine. Veh + Hal (0.03) 113 (+25) However, aripiprazole, when combined with a fixed dose of Pim + Hal (0.0003) 17 (+6) <10 pimavanserin (0.03 mg/kg, filled squares), demonstrated an Pim + Hal (0.001) 14 (+4) 11 (+3) enhanced Suppression of amphetamine-induced hyperloco Pim + Hal (0.003) 25 (+5) 12 (+4) Pim + Hal (0.01) 14 (+6) 45 (+7) motor activity. (0189 The raw data contained in FIG. 15A were converted to % MPI to generate dose-response curves depicted in FIG. US 2015/0231126 A1 Aug. 20, 2015

15B. Aripiprazole (open Squares) produced a dose-dependent Example 5 attenuation of hyperactivity elicited by amphetamine. How ever, when combined with a fixed dose of pimavanserin (0.03 Attenuation of Other Side Effects when mg/kg, filled squares), the dose-response curve for aripipra Pimavanserin is Co-Administered with Zole was significantly shifted to the left. Antipsychotics 0.190 FIG. 16A is graph illustrating the distance traveled as a function of quetiapine dose for the various administered Prolactin Assay agents. Relative to vehicle controls (open circle), amphet 0196. Dose response curves were generated for haloperi amine (open triangle) significantly increases hyperlocomotor dol, risperidone and pimavanserin on serum prolactin levels. activity in mice. Pimavanserin at a dose of 0.03 mg/kg (filled Rats were dosed ip with vehicle (100% dimethylsulfoxide) circle) failed to Suppress hyperlocomotion produced by haloperidol or risperidone, while pimavanserin or vehicle amphetamine. In contrast, quetiapine (open squares) dose (saline) was given sc. Blood samples were collected 30 min dependency attenuated hyperactivity produced by amphet following vehicle, haloperidol or risperidone administration amine. However, quetiapine, when combined with a fixed or 60 min after pimavanserin administration. Rats were dose of pimavanserin (0.03 mg/kg, filled squares), demon deeply anesthetized with and blood samples were strated an enhanced suppression of amphetamine-induced obtained by cardiac puncture, allowed to clot and then cen hyperlocomotor activity. trifuged at 12,000 rpm for 10 minto yield serum for analysis. 0191 The raw data contained in FIG.16A were converted Serum prolactin levels were quantified using a commercially to % MPI to generate dose-response curves depicted in FIG. available enzyme immunoassay kit (ALPCO Diagnostics, 16B. Quetiapine (open squares) produced a dose-dependent Windham, N.H.). attenuation, of hyperactivity elicited by amphetamine. How 0.197 In order to explore the potential interaction between ever, when combined with a fixed dose of pimavanserin (0.03 haloperidol or risperidone and pimavanserin on serum pro mg/kg, filled squares), the dose-response curve forquetiapine lactin levels, rats were dosed sc with either vehicle or various was shifted to the left. doses of pimavanserin, then 30 min later, dosed ip with either 0.192 The effects of quetiapine and pimavanserin, alone vehicle or a fixed dose of haloperidol or risperidone. Blood and in combination, on Suppression of dizocilpine-induced samples were collected 30 min following vehicle, haloperidol hyperlocomotion in mice was also evaluated. Isobolographic or risperidone administration (i.e., 60 min following vehicle analysis was conducted and the resulting isobologram is pre or pimavanserin administration). The time point for sample sented in FIG. 17. The calculated ID and (95% CI) values collection was chosen based on our work and that of others for pimavanserin and quetiapine when administered alone (Liegeois et al., 2002b), which show that 30 minappears to be (open Squares) are plotted on the X- and y-axes, respectively. the time at which peak prolactin levels can be detected fol The dashed line connecting these two points represents the lowing risperidone or haloperidol treatment, respectively. line of theoretical additivity. The experimental IDs (filled The fixed doses of haloperidol (0.1 mg/kg) and risperidone square, B) for the dose combination was not significantly (0.01 mg/kg) were chosen since they elicited statistically different than the theoretical IDs (filled circle, A), indicating significant and reproducible, but Sub-maximal, increases in an additive interaction. prolactin, thus allowing for the detection of potential increases as well as decreases. Example 4 Effects of Haloperidol and Risperidone Alone, and in Use of Pimavanserin for Reversing Cognitive Combination with Pimavanserin, on Serum Prolactin Impairment in Mice Administered Anti-Psychotics Levels in Rats 0193 Various antipsychotics were administered alone or 0198 FIG. 20A is a graph depicting the dose response of in combination with pimavanserinto mice in an in vivo mouse prolactin levels obtained in rats following various doses of model of cognition. Compounds were administered to mice at risperidone (filled squares), haloperidol (open squares) and one hour post-training (a time-point at which animals nor pimavanserin (filled circles). Serum prolactin levels obtained mally behaviorally discriminate between novel and familiar in vehicle-treated controls were 24+3 ng/mL and 31+3 ng/mL objects) and two hours post-training (a time-point at which after 30 min and 60 min, respectively. As expected, 60 min these animals normally no longer discriminate between following haloperidol treatment rats demonstrated a dose objects). related increase in serum prolactin levels as compared to 0194 FIG. 18 is a bar graph of percent novel object rec vehicle controls. Similarly, 30 min following risperidone ognition upon administration of vehicle, pimavanserin (0.3 treatment, a dose-dependent increase in serum prolactin lev mg/kg), risperidone, olanzapine, and combinations of pima els was observed. In contrast, pimavanserin treatment, up to 3 Vanserin with risperidone or olanzapine. The results indicate mg/kg, did not significantly elevate serum prolactin levels as that pimavanserin reverses novel object recognition impair compared to vehicle-treated controls. Rather, rats treated with ment caused by risperidone and olanzapine. pimavanserin demonstrated a significant reduction in serum 0.195 Combinations of pimavanserin and risperidone prolactin concentrations, as the values obtained were 31+3 were also evaluated in a radial arm maze in vivo mouse model ng/mL and 15-0 ng/mL after vehicle and 3 mg/kg pimavan of cognition. FIG. 19 is a graph indicating working memory serin, respectively. Allrats treated with 3 mg/kg pimavanserin errors after repeated trials upon administration of vehicle, had serum prolactin concentrations below the limit of detec risperidone, pimavanserin (1 mg/kg), and combination of tion; hence a value of 15 ng/ml was assigned. risperidone with pimavanserin. The results indicated that (0199 FIG. 20B depicts the serum prolactin levels pimavanserin improved the cognitive deficit induced by ris obtained in rats following fixed doses of risperidone (0.0.1 peridone. mg/kg, tilled bars) or haloperidol (0.1 mg/kg, open bars) in US 2015/0231126 A1 Aug. 20, 2015 20 the presence of vehicle or various doses of pimavanserin. Discussion Each data point represents a minimum n of 12. ** denotes 0203 Antagonism of D, receptors produces robust pro p-0.001: * denotes p-0.05. The dose of haloperidol signifi lactinemia both experimentally and clinically. Similarly, ris cantly increased serum prolactin levels from 313 ng/mL to peridone, an atypical APD, has also been shown to elicit 102-12 ng/mL. Similarly, risperidone significantly increased prolactinemia as severe as haloperidol in humans. In the serum prolactin levels from 24+3 ng/mL to 102+12 ng/mL. present investigation, it was demonstrated that while both However, in the presence of pimavanserin, at doses consistent haloperidol and risperidone produced robust increases in with 5-HT2 receptor blockade, the magnitude of prolactine serum prolactin, pimavanserin alone did not elevate, and mia induced by either haloperidol or risperidone was signifi indeed slightly reduced, serum prolactin levels. Importantly, cantly attenuated. pimavanserin did not potentiate, but rather attenuated the hyperprolactinemia produced by these APDs. Despite the Catalepsy Assessment anatomical evidence Supporting expression of 5-HT2 recep tors in the pituitary gland, the preponderance of data Suggests 0200 Rats were positioned with their forepaws on a hori that the regulation of prolactin secretion mediated by 5-HT, Zontal bar (diameter 10 mm); elevated 10 cm above the bench receptors occurs at the level of the hypothalamus. Pituitary D. top, and the duration of the cataleptic bout was recorded up to receptors, which lie outside of the blood brain barrier (BBB), a maximum catalepsy value of 120 sec. Catalepsy values exert tonic inhibition of prolactin secretion, while activation (CVs) were obtained at 30 and 60 min following ip adminis of 5-HT, receptors in the hypothalamus inhibits DA release tration risperidone or haloperidol, respectively. Doses of resulting in prolactin elevation. Thus, pure D antagonists pimavanserin were administered sc 60 min prior to either elicit prolactinemia by direct actions in the pituitary, whereas, haloperidol or risperidone. In order to generate dose-response highly brain penetrating APDs, especially those which pos sess high 5-HT/D affinity ratios (i.e., olanzapine and curves raw CVs were converted to percentage maximum pos clozapine), do not elicit marked hyperprolactinemia because sible catalepsy (% MPC): % MPC=((CV drug or drug com these drugs achieve sufficient 5-HT, receptor blockade in bination-CV vehicle control)/(120-CV vehicle control)) the hypothalamus to counteract the effects of D receptor * 100. The dose that elicits 50% of maximum catalepsy blockade in the pituitary. This is critical with respect to ris (CDs) and the corresponding 95% CI was determined for peridone which has been shown to preferentially occupy D. each compound as previously mentioned. Each dose or dose receptors in the pituitary gland, as compared to the striatum, combination was assessed in separate groups of rats. at doses up to 2.5 mg/kg in rats. If risperidone does indeed poorly cross the BBB then the profile of this drug is more Effects of Pimavanserin on Haloperidol- and consistent with a typical, rather than an atypical APD, as the Risperidone-Induced Catalepsy in Rats direct effects at D in the pituitary are not likely to be coun teracted by 5-HT, receptor blockade inside the BBB. Con 0201 FIG.21A depicts dose response curves as a function sistent with this idea are the observations in the present study of haloperidol dose AS expected, haloperidol (open circles) in which it was shown that risperidone elevates prolactin at produced a dose-dependent increase in catalepsy time in rats. doses equal to or below those required to attenuate head Pimavanserin failed to potentiate haloperidol-induced cata twitches produced by DOI. Furthermore, by combining pima vanserin with risperidone a sufficient level of 5-HT, receptor lepsy at any of the doses tested. The combination of 1 (filled occupancy was reached inside the BBB to counteract risperi circles) or 3 mg/kg (open squares) of pimavanserin with halo done-induced hyperprolactinemia. Taken together, these data peridol did not significantly alter haloperidol-induced cata indicate that risperidone is not likely to achieve maximum lepsy, CDs values of 0.24 mg/kg (0.016-0.36; 95% CI) and occupancy of 5-HT, receptors inside the BBB, in the 0.38 mg/kg (0.24-0.61; 95% CI), respectively. However, the absence of significant D receptor antagonism, in rats or in addition of 10 mg/kg pimavanserin (filed squares) to halo humans. These finding have significant clinical relevance, as peridol significantly increased the observed CHso values hyperprolactinemia is correlated with numerous complica from 0.27 mg/kg (0.19-0.39; 95% CI) to 0.53 mg/kg (0.31-0. tions such as sexual dysfunction, which is a prominent cause 91; 95% CI) indicating a reduction of catalepsy. of noncompliance, particularly in men, with these medica 0202 FIG.21B depicts dose response curves as a function tions. of risperidone dose. As expected, risperidone (open circles) 0204 Finally, this investigation demonstrated that while produced a dose-dependent increase in catalepsy time in rats. both haloperidol and risperidone produced dose-dependent Each data point represents a minimum n of 12. Vehicle treat catalepsy, pimavanserin alone did not elicit detectable cata ment elicited a maximum CV of 6.8+0.9 sec. Pimavanserin lepsy at doses as high as 10 mg/kg, or 50-fold higher than the did not elicit catalepsy at doses up to 10 mg/kg achieving a IDs in a DOI head twitch assay, consistent with its lack of affinity for D, receptors. It was demonstrated that although maximum CV of 10.5+2.4 sec, a value that was not signifi pimavanserin potentiated the efficacy of haloperidol and ris cantly different from that obtained in vehicle treated controls. peridone, pimavanserin clearly did not potentiate the cata In contrast, both haloperidol and risperidone produced dose lepsy produced by either drug. Instead, a small but significant dependent and marked increases in CVs yielding CDso values reduction of haloperidol-induced catalepsy at a dose of pima of 0.27 mg/kg (0.19-0.39; 95% CI) and 1.1 mg/kg (0.79-1.62: vanserin was observed that would be expected for supramaxi 95% CI), respectively. Pimavanserin, at all doses tested, mal 5-HT, receptor occupancy (i.e., 10 mg/kg). Pimavan resulted in a dose-dependent and significant rightward dis serin demonstrates approximately 50-fold selectivity for placement of the risperidone dose response curve for cata 5-HT, over 5-HT. This result suggests that the attenuation lepsy. The calculated CDso values for risperidone in the pres of catalepsy by pimavanserin may be driven by its weaker ence of 1 (filled circles), 3 (open squares) or 10 mg/kg (filled 5-HT, receptor interactions. Based on the in vivo data, the squares) pimavanserin were 2.0 mg/kg (1.3-3.0; 95% CI), 4.4 selectivity of pimavanserin for 5-HT, over 5-HT, receptors mg/kg (2.6-7.5: 95% CI) and 5.1 mg/kg (3.2-8.3: 95% CI), would be approximately 50-fold, which is in agreement with respectively, indicating a reduction of catalepsy. previously published in vitro data. Pimavanserin also pro US 2015/0231126 A1 Aug. 20, 2015

duced a significant attenuation of risperidone-induced cata TABLE 5 lepsy, however, at doses as low as 1 mg/kg. The apparent shift in potency shown by pimavanserin against risperidone-in Initial parameters used in simulation plasma duced catalepsy is likely a function of the excess of 5-HT concentration-time profile of pimavanserin following antagonist expected to be present at doses of risperidone that oral administration of 20 mg of pinavanserin once daily. would presumably occupy >70% of striatal D receptors. Parameter Value Therefore, in a system that is in far excess of maximal 5-HT receptor occupancy, as would be expected with these dose V/F (mL) 2182727 combinations, weaker 5-HT, antagonist properties of pima KO1 (1/hr) O.91.97 Vanserin, and perhaps risperidone, are more likely to mani CLF (mL/hr) 26411: fest. *Calculated using DAUC(0-24)ss Example 6 Plasma Concentration-Time Profile Following Oral Prolactin Levels during Co-Administration of Administration of 5 mg of Risperidone Once Daily Pimavanserin with Risperidone 0209 Initial parameters for the simulation were obtained 0205 Prolactin levels were measured during a Phase II by fitting mean plasma concentration-time data to a 2-com Schizophrenia co-therapy trial using pimavanserin in combi partment model (first order input, micro-constants, no lag nation with risperidone and compared to administration of time and first orderelimination). Mean plasma concentration risperidone alone. As depleted in the FIG. 22 graph, patients time data obtained following administration of a single oral in the co-therapy arm with pimavanserin plus risperidone (2 dose of 4 mg of risperidone were applied. Based on the model, mg) had significantly lower prolactin levels after 42-days of the pharmacokinetic parameters shown, in Table 6 were esti treatment as compared to patients in the risperidone (6 mg) mated. plus placebo arm (p=0.0001). TABLE 6 Example 7 Pharmacokinetic parameters obtained by fitting risperidone mean plasma concentration-time data to a 2-compartment model Simulation of Pimavanserin and Risperidone Steady State Plasma Concentrations and 5-HT2A and D2 Pharmacokinetic parameter Estimate Receptor Occupancy Following Co-Administration Absorption rate constant O4403 (k01) (1/hr) Plasma Concentration-Time Profile Following Oral Elimination rate constant O.2393 (k01) (1/hr) Administration of 20 mg of Pimavanserin Once Alpha (1/hr) O4314 Daily Beta (1/hr) O.O349 CLF (L/hr) 14408.8 0206. Initial parameters for the simulation were obtained V2/F (mL) 157245.7 by fitting mean plasma concentration-time data to a 1-com CLD2/F (mL/hr) 9885.5 partment model (first order input, no lag time and first order Tmax (hr) 2.4 elimination). Mean multiple-dose plasma concentration-time Cmax (ng/mL) 25.8 data following the 14" oral dose of 50 mg of pimavanserin AUC (hr ng/mL) 277.6 were applied. Based on the model, the pharmacokinetic parameters shown in Table 4 were estimated. 0210. The pharmacokinetic parameters provided in Table 6 agreed reasonably well with previous reported pharmaco TABLE 4 kinetic parameters for risperidone. However, the secondary parameters were poorly estimated by the model as indicated Pharmacokinetic parameters obatined by fitting pimavanserin mean plasma by the coefficient of variation of the parameters. concentration-time data (50 mg) to 1-compartment model. 0211. The plasma concentration-time profile of risperi Pharmacokinetic parameter Estimate done following oral administration of 5 mg of risperidone once daily was simulated using the initial parameters pro Absorption rate constant (k01) (1/hr) O.91.97 vided in Table 7. The simulated profile for risperidone admin Elimination rate constant (k01) (1/hr) O.O121 istered alone are shown in FIG. 23. CLF (L/hr) 6.4 Tmax (hr) 4.77 Cmax (ng/mL) 89.27 TABLE 7 AUC (0-24)ss (hr ng/mL) 1893.2 Initial parameters used in simulation of plasma concentration-time profile of risperidone following 0207. The pharmacokinetic parameters provided in Table oral administration of 5 mg of risperidone once daily. 4 agreed well with previous reported pharmacokinetic param eters obtained following multiple oral doses of pimavanserin. Parameter Value One exception is the oral clearance for which the estimated V1/F (mL) 60222 parameter is somewhat lower compared to the previous KO1 (1/hr) O4403 reported value (25.2 L/hr). CLF (mL/hr) 14409 0208. The plasma concentration-time profile of pimavan V2/F (mL) 157246 serin following oral administration of 20 mg of pimavanserin CLD2/F (mL/hr) 9886 once dally was simulated using the initial parameters pro vided in Table 5. The simulated profile for pimavanserin 0212. Due to the shorter half-life of risperidone, 19.9 hr administered alone are shown in FIG. 23. compared to 57.3 for pimavanserin, fluctuations between US 2015/0231126 A1 Aug. 20, 2015 22 peak and trough plasma concentrations are seen to be higher decreases as compared to the higher dose of risperidone for risperidone. Steady state concentrations of pimavanserin administered alone (see FIG. 24) while the 5HT receptor are reached following approximately 200hr corresponding to occupancy is maintained at high level. These results Support 8 days. Cass and Cass for pimavanserin are approxi that the combination can lead to a lower incidence of D2 mately 27.2 and 34.5 ng/mL, respectively. The steady state related side effects without affecting 5HT associated efficacy. maximum concentrations are reached approximately 4 hours 0220. The D2 receptor occupancy was calculated using post dosing. equation 1. The 5HT receptor occupancy was calculated using equation 3: D-(CR/(CR +Kdsz (1+CR2/Kdst 12)) Simulation of the Time Course of Serotonin 5-HT2A +(Cr2/Cr2+Kds(1+C/Kdsz))*100, where C, C2, and Dopamine D2 Receptor Occupancy from Plasma Kds, Kds is the unbound concentration of pimavan Pharmacokinetics of Pimavanserin and Risperidone serin, unbound concentration of risperidone, dissociation constant of pimavanserin for 5HT2A receptor and dissocia 0213. The receptor occupancy (d. 96) was calculated tion constant of risperidone for 5HT2A, respectively. using equation 1, d=(C/C+Kd)*100, where C is the con 0221) Several other doses of risperidone were also evalu centration of unbound drug around the receptor (nM) and Kd ated. The D3 and 5HT receptor occupancy-time profiles fol is the dissociation constant (nM). lowing therapy with 3 mg twice dally of risperidone alone is 0214 C is assumed to equal the unbound drug concen shown in FIG. 26A. The D2 and 5HT receptor occupancy tration in plasma implying that equilibrium between plasma time profiles following combined therapy with pimavanserin and brain is last and no active transport of the drug takes place and risperidone is shown in FIG. 26B. The pimavanserin dose during distribution to the brain. C may then be calculated was maintained at 20 mg daily, and the risperidone dose was using equation 2, Co. f*C.(t), wheref, is the free fraction of maintained at 3 mg twice daily. The contribution from pali rug in plasma and C?(t) is the plasma concentration at time t. peridone to the receptor profiles was not taken into account. 0215. The 5HT2A and D2 receptor occupancies of pima FIGS. 26A and 26B illustrate that receptor occupancy of 5HT Vanserin and risperidone were estimated using the parameters was enhanced with combined pimavanserin and risperidone in Table 7 and the Cf(t) obtained above. therapy versus risperidone therapy alone when dosing at 3 mg twice daily. Notably, due to the long action of the low half-life TABLE 7 pimavanserin, the variation in 5HT receptor occupancy Unbound fraction in plasma and Kd decreased in the combination. The receptor occupancy of D2 of pimavanserin and risperidone remained substantially unchanged. 0222. The D2 and 5 HT receptor occupancy-time profiles Kd (nM for paliperidone (a metabolite of risperidone) following f, SHT2A D2 therapy with risperidone alone at 3 nig twice daily is shown in FIG.27A. The risperidone dose was maintained at 3 mg twice Pimavanserin O.OS 0.4 daily. The D2 and 5HT receptor occupancy-time profiles for Risperidone O.1 O.2 O.3 paliperidone following combined therapy with pimavanserin and risperidone is shown in FIG.27B. The pimavanserin dose 0216. The receptor occupancy-time profile of pimavan was maintained at 20 mg daily, and the risperidone dose was serin (20 mg/24hr) and risperidone (5 mg/24hr) when admin maintained at 3 mg twice daily. The contribution from ris istered separately is shown in FIG. 24. Risperidone, which peridone to the receptor profiles was not taken into account acts at both D2 and 5HT receptors, achieved high occupancy FIGS. 27A and 27B further illustrate that receptor occupancy at both receptors. Pimavanserin, which has a longer half life of 5HT was slightly enhanced with combined pimavanserin than risperidone, showed less variability in 5HT receptor and risperidone therapy versus risperidone therapy alone Occupancy. when dosing at 3 mg twice daily. The receptor occupancy of 0217. Following the first oral dose of 20 mg of pimavan D2 remained Substantially unchanged. serin 71% 5HT2A receptor occupancy is achieved 5 hr post 0223) The D2 and 5HT receptor occupancy-time profiles dosing (tmax). The corresponding plasma concentration of following therapy with risperidone with 3 mg twice daily pimavanserin (Cmax) is 8.6 ng/mL. Steady state 5HT2A taking into consideration both risperidone and paliperidone is receptor occupancies for pimavanserin vary between 88% shown in FIG. 28A. The D2 and 5HT receptor occupancy and 91%. time profiles following combined therapy with pimavanserin 0218. The calculated occupancy of 5HT2A and D2 recep and risperidone is shown in FIG. 28B. The pimavanserin dose tors 2.4 hours after the first oral dose of 5 mg of risperidone is was maintained at 20 mg daily and the risperidone dose was 98% and 90%, respectively. The corresponding plasma con maintained at 3 mg twice daily. FIGS. 28A and 28B further centration of risperidone is 32.3 ng/mL. The steady state D2 illustrate that receptor occupancy of 5HT was slightly receptor occupancy of risperidone ranges between 80% and enhanced with combined pimavanserin and risperidone 97%. Occupancy of the 5HT receptor in steady state is therapy versus risperidone therapy alone when dosing at 3 mg between 86% and 98%. The corresponding minimum and twice dally. The receptor occupancy of D2 remained substan maximum steady state plasma concentrations of risperidone tially unchanged. are 4.9 ng/mL and 36.6 ng/mL. 0224. The D2 and 5HT receptor occupancy-time profiles 0219. The receptor occupancy-time profile of D2 and 5HT following therapy with 1 mg twice daily of risperidone alone receptors following combined therapy with pimavanserinand is shown in FIG. 29A. The D2 and 5HT receptor occupancy risperidone is shown in FIG. 25. The pimavanserin dose was time profiles following combined therapy with pimavanserin maintained at 20 mg once daily as in FIG. 24, whereas the and risperidone is shown in FIG.29B. The pimavanserin dose daily dose of risperidone has been reduced to 1 mg once daily. was maintained at 20 mg daily and the risperidone dose was The results indicate that D2 receptor occupancy significantly maintained at 1 mg twice daily. For FIGS. 29A and 29B, the US 2015/0231126 A1 Aug. 20, 2015 contribution from paliperidone to the receptor profiles was variability in 5-HT2A receptor occupancy, allowing the high not taken into account. FIGS. 29A and 29B illustrate that levels of occupancy to be maintained between dosings. receptor occupancy of 5HT was significantly enhanced with 0228. Although the invention has been described with ref combined pimavanserin and risperidone therapy versus ris peridone therapy alone at 1 mg twice daily dosing. The varia erence to embodiments and examples, it should be under tion in 5HT receptor occupancy decreased substantially in the stood that numerous and various modifications can be made combination, demonstrating the beneficial effect of combin without departing from the spirit of the invention. Accord ing the long acting pimavanserin with the short acting risperi ingly, the invention is limited only by the following claims. done. The receptor occupancy of D2 remained Substantially What is claimed is: unchanged. Comparison with FIG. 26B (illustrating a 3 mg 1. A method of treating a condition amenable to treatment twice daily dose of risperidone) illustrates a more significant with an antipsychotic, comprising: enhancement in 5HT receptor occupancy with a decreased administering a first amount of a 5-HT2A inverse agonist D2 receptor occupancy. or antagonist, and 0225. The D2 and 5HT receptor occupancy-time profiles administering a second amount of an antipsychotic agent, for paliperidone following therapy with 1 mg twice dally wherein the first and second amounts are such that an risperidone alone is shown in FIG. 30A. The D2 and 5HT efficacious effect is achieved faster than when the antip receptor occupancy-time profiles for paliperidone following sychotic agent is administered alone at an efficacious combined therapy with pimavanserin and risperidone is dose. 2. The method of claim 1, wherein the second amount is shown in FIG.30B. The pimavanserin dose was maintained at less than a maximal dose of the antipsychotic agent when it is 20 mg daily and the risperidone dose was maintained at 1 mg administered alone. twice daily. For FIGS. 30A and 30B, the contribution from 3. The method of claim 1, wherein the second amount is risperidone to the receptor profiles was not taken into less than an efficacious dose of the antipsychotic agent when account. FIGS. 30A and 30B illustrate that receptor occu it is administered alone. pancy of 5HT was significantly enhanced with combined 4. The method of claim 1, wherein the first and second pimavanserin and risperidone therapy versus risperidone amounts are such that the severity or onset of one or more side therapy alone at 1 mg twice daily dosing. A decrease in 5HT effects due to the antipsychotic agent are reduced as com receptor occupancy variation was also observed in the com pared to administration of an efficacious dose of the antipsy bination. The receptor occupancy of D2 remains substantially chotic agent alone. unchanged. Comparison with FIG. 27B (illustrating a 3 mg 5. The method of claim 4, wherein the side effect is weight twice daily dose of risperidone) illustrates a more significant gain. enhancement in 5HT receptor occupancy with a decreased 6. The method of claim 4, wherein the side effect is selected D2 receptor occupancy. from the group consisting of an extrapyramidal side effect, a 0226. The D2 and 5HT receptor occupancy-time profiles histamine side effect, an alpha adrenergic side effect, and an following therapy with 1 mg twice daily taking both risperi anticholinergic side effect. 7. The method of claim 4, wherein the side effect is selected done and paliperidone into account is shown in FIG.31A. The from the group consisting of stroke, tremors, sedation, gas D2 and 5HT receptor occupancy-time profiles following trointestinal problems, neurological problems, increased risk combined therapy with pimavanserin and risperidone is of death, cerebrovascular events, movement disorder, dysto shown in FIG.31B. The pimavanserin dose was maintained at nia, akathisia, parkinsoniam movement disorder, tardive dys 20 mg daily and the risperidone dose was maintained at 1 mg kinesia, cognitive disorders, prolactinemia, catalepsy, psy twice daily. FIGS. 31A and 31B illustrate that receptor occu chosis, neuroleptic malignant syndrome, heart problems, pancy of 5HT was significantly enhanced with combined pulmonary problems, diabetes, liver failure, Suicidality, seda pimavanserin and risperidone therapy versus risperidone tion, orthostatic hypotension, choking, dizziness, tachycar therapy alone at 1 mg twice daily dosing. A decrease in 5HT dia, blood abnormalities, abnormal triglyceride levels, increased cholesterol levels, dyslipidemia, hyperglycemia, receptor occupancy variation was also observed in the com Syncope, seizures, dysphagia, priapism, thrombotic thromb bination. The receptor occupancy of D2 remained Substan ocytopenic purpura, disruption of body temperature regula tially unchanged. Comparison with FIG. 28B (illustrating a 3 tion, insomnia, agitation, anxiety, Somnolence, aggressive mg twice daily dose of risperidone) illustrates a more signifi reaction, headache, constipation, nausea, dyspepsia, vomit cant enhancement in 5HT receptor occupancy with a ing, abdominal pain, saliva increase, toothache, rhinitis, decreased D2 receptor occupancy. coughing, sinusitis, pharyngitis, dyspnea, back pain, chest 0227 Taken together, FIGS. 24-31B demonstrate that pain, fever, rash, dry skin, seborrhea, increased upper respi combinations of pimavanserin and low doses of risperidone ratory infection, abnormal vision, arthralgia, hypoaesthesia, can result in an enhancement of the receptor occupancy of the manic reaction, concentration impairment, dry mouth, pain, 5HT2A receptor compared with low dose risperidone therapy fatigue, acne, pruritus, myalgia, skeletal pain, hypertension, alone and achieve a lower D2 receptor occupancy due to the diarrhea, confusion, asthenia, urinary incontinence, sleepi ness, increased duration of sleep, accommodation distur lower dose of risperidone. Thus, a combined therapy with bance, palpitations, erectile dysfunction, ejaculatory dys pimavanserin and risperidone can increase the efficacy of function, orgastic dysfunction, lassitude, increased anti-psychotic treatment without increasing side effects due pigmentation, increased appetite, automatism, increased to D2 receptor occupancy. Furthermore, the results demon dream activity, diminished sexual desire, nervousness, strate that combining the long acting drug pimavanserin with depression, apathy, catatonic reaction, euphoria, increased the short acting drug risperidone results in significantly less libido, amnesia, emotional liability, nightmares, delirium, US 2015/0231126 A1 Aug. 20, 2015 24 yawning, dysarthria, Vertigo, stupor, paresthesia, aphasia, 13. The method of claim 1, wherein the 5-HT2A inverse hypoesthesia, tongue paralysis, leg cramps, torticollis, hypo agonist or antagonist is a compound selected from the group tonia, coma, migraine, hyperreflexia, choreoathetosis, anor consisting of: exia, flatulence, stomatitis, melena, hemorrhoids, gastritis, fecal incontinence, erutation, gastroeophageal reflux, gastro enteritis, esophagitis, tongue discoloration, choleithiasis, tongue edema, diverticulitis, gingivitis, discolored feces, gas trointestinal hemorrhage, hematemesis, edema, rigors, mal aise, pallor, enlarged abdomen, ascites, sarcoidosis, flushing, hyperventilation, bronchospasm, pneumonia, tridor, asthma, increased sputum, aspiration, photosensitivity, increased Sweating, acne, decreased Sweating, alopecia, hyperkerato sis, skin exfoliation, bullous eruption, skin ulceration, aggra vated psoriasis, furunculosis, Verruca, dermatitis lichenoid, O hypertrichosis, genital pruritus, urticaria, Ventricular tachy and cardia, angina pectoris, premature atrial contractions, T wave inversion, ventricular extrasystoles, ST depression, AV block, myocarditis, abnormal accommodation, Xerophthalmia, diplopia, eye pain, blepharitis, photopsia, photophobia, abnormal lacrimation, hyponatremia, creatine phosphoki nase increase, thirst, weight decrease, decreased serum iron, cachexia, dehydration, hypokalemia, hypoproteinemia, hyperphosphatemia, hypertrigylceridemia, hyperuricemia, hypoglycemia, polyuria, polydipsia, hemturia, dysuria, uri nary retention, cystitis, renal insufficiency, arthrosis, Synos tosis, bursitis, arthritis, menorrhagia, dry vagina, nonpeurp eral lactation, amenorrhea, female breast pain, leukorrhea, mastitis, dysmenorrhea, female perineal pain, intermenstrual 14. The method of claim 1, wherein the 5-HT2A inverse bleeding, vaginal hemorrhage, increased SGOT, increased agonist orantagonist is selected from the group consisting of SGPT. cholestatic hepatitis, cholecystitis, choleithiasis, hepa Adatanserin, Altanserin, Benanserin, Blonanserin, titis, hepatocellular damage, epistaxis, Superficial phlebitis, Butanserin, Cinanserin, Eplivanserin, Fananserin, Fli thromboplebitis, thrombocytopenia, tinnitus, hyperacusis, banserin, Glemanserin, Iferanserin, Ketanserin, Lidanserin, Mianserin, Pelanserin, Pruvanserin, Ritanserin, Seganserin, decreased hearing, anemia, hypochromic anemia, nor and Tropanserin. mocytic anemia, granulocytopenia, leukocytosis, lymphad 15. The method of claim 1, wherein the antipsychotic agent enopathy, leucopenia, Pelger-Huet anomaly, gynecomastia, is a typical antipsychotic. male breast pain, antiduretic hormone disorder, bitter taste, 16. The method of claim 1, wherein the antipsychotic agent micturition disturbances, oculogyric crisis, abnormal gait, is an . involuntary muscle contraction, and increased injury. 17. The method of claim 1, wherein the antipsychotic agent 8. The method of claim 1, wherein the condition is psycho is a D2 antagonist. sis and the efficacious effect is an antipsychotic effect. 18. The method of claim 1, wherein the antipsychotic agent 9. The method of claim 8, wherein, the psychosis is asso is risperidone. ciated with Schizophrenia. 19. The method of claim 1, wherein the antipsychotic agent is haloperidol. 10. The method of claim 8, wherein the psychosis is acute 20. The method of claim 1, wherein the antipsychotic agent psychotic exacerbation. is selected from the group consisting of a phenothiazine, a 11. The method of claim 1, wherein the 5-HT2A inverse phenylbutylpiperidine, a dibenzapine, a benzisoxidil, and a agonist of antagonist is the compound of formula (I): salt of lithium. 21. The method of claim 20, wherein the phenothiazine is selected from the group consisting of chlorpromazine (Thora (I) zine(R), mesoridazine (Serentil(R), prochlorperazine (Com pazine(R), thioridazine (Mellaril), Fluphenazine (Prolixin R), CH3 Perphenazine (Trilafon(R), and Trifluoperazine (Stelazine(R). 22. The method of claim 20, wherein the phenylbutylpip eridine is pimozide (OrapR). 23. The method of claim 20, wherein the dibenzapine is selected from the group consisting of clozapine (CloZarilR), loxapine (LOXitane(R), olanzapine (ZyprexaR), and quetiap ine (Seroquel(R). 24. The method of claim 20, wherein the benzisoxidil is ziprasidone (Geodon(R). 25. The method of claim 20, wherein the salt of lithium is lithium carbonate. 12. The method of claim 11, wherein the antipsychotic 26. The method of claim 1, wherein the antipsychotic agent agent is risperidone. is selected from the group consisting of Aripiprazole US 2015/0231126 A1 Aug. 20, 2015

(Abilify(R), Etrafon R, Droperidol (Inapsine(R). Thioridazine a greater percentage of patients experience an efficacious (MellarilR). Thiothixene (Navane(R). Promethazine (Phener effect than when the antipsychotic agent is administered gan.R.), Metoclopramide (ReglanR), Chlorproxthixene (Ta alone at an efficacious dose. ractan(R), Triavil(R), Molindone (Moban.(R), Sertindole (Ser 36. The method of claim 35, wherein the 5-HT2A inverse lect(R), Droperidol, Amisulpride (SolianR), Melperone, agonist or antagonist is the compound of formula (1): Paliperidone (InvegaR), and Tetrabenazine. 27. The method of claim 1, wherein the condition amenable (I) to treatment is selected from the group: consisting of schizo CH phrenia, bipolar disorder, agitation, psychosis, behavioral disturbances in Alzheimer's disease, depression with psy N chotic features or bipolar manifestations, obsessive compul sive disorder, post traumatic stress syndrome, anxiety, per Sonality disorders (borderline and Schizotypal), dementia, dementia with agitation, dementia in the elderly, Tourette's H syndrome, restless leg syndrome, insomnia, Social anxiety N N disorder, dysthymia, ADHD and autism. 28. The method of claim 1, wherein the administration is to O a human less than eighteen years of age. 29. The method of claim 1, comprising identifyingapatient 37. The method of claim 35, wherein the antipsychotic in need of a rapid onset of antipsychotic action. agent is risperidone. 38. A method of reducing or preventing weight gain asso 30. A method of inducing a rapid onset of an antipsychotic ciated with administration of an antipsychotic agent, com effect, comprising co-administering a 5-HT2A inverse ago prising co-administering a 5-HT2A inverseagonist orantago nist or antagonist and an antipsychotic agent to a subject nist with the antipsychotic agent to a Subject at risk or of Suffering from psychosis such that there is a rapid onset of Suffering from weight gain associated with administration of antipsychotic effect. an antipsychotic agent. 31. The method of claim 30, wherein the 5-HT2A inverse 39. The method of claim 38, wherein the 5-HT2A inverse agonist or antagonist is the compound of formula (I): agonist or antagonist is the compound of formula (I): (I) (I) CH3 CH N

H N N

to O or O 32. The method of claim 30, wherein the antipsychotic 40. The method of claim 38, wherein the antipsychotic agent is risperidone. agent is risperidone. 33. A method of inducing a rapid onset of an antidepressant 41. A method of increasing patient compliance during effect, comprising co-administering a 5-HT2A inverse ago antipsychotic therapy, comprising, co-administering a nist or antagonist and an antipsychotic agent to a subject 5-HT2A inverse agonist or antagonist with an antipsychotic Suffering from depression Such that there is a rapid onset of agent, wherein the doses of co-administration are Such that antidepressant effect. patient compliance is increased as compared to compliance 34. The method of claim 33, wherein the 5-HT2A inverse when administering an efficacious dose of the antipsychotic agonist or antagonist is the compound of formula (I): agent alone. 42. The method of claim 41, wherein the 5-HT2A inverse (I) agonist or antagonist is the compound of formula (I): CH3 (I) CH

to O or 35. A method of increasing the percentage of patients to O or responding to antipsychotic therapy, comprising co-adminis tering a 5-HT2A inverse agonist or antagonist and an antip 43. The method of claim 41, wherein the antipsychotic sychotic agent to a Subject Suffering from psychosis such that agent is risperidone. US 2015/0231126 A1 Aug. 20, 2015 26

44. A method of reducing or preventing hyperprolactine 51. The method of claim 50, wherein the antipsychotic mia caused by administration of risperidone, comprising co agent is risperidone. administering a 5-HT2A inverse agonist or antagonist with 52. A pharmaceutical composition, comprising: less than 6 mg per day of risperidone to a Subject at risk of or a first amount of a 5-HT2A inverse agonist or antagonist; Suffering from hyperprolactinemia associated with adminis and tration of risperidone. a second amount of an antipsychotic agent, wherein the 45. The method of claim 44, wherein the 5-HT2A inverse first and second amounts are such that when the compo agonist or antagonist is the compound of formula (1): sition is administered, an efficacious antipsychotic effect is achieved faster than when the antipsychotic agent is administered alone at an efficacious dose. (I) 53. The pharmaceutical composition of claim 52, wherein CH the second amount is less than a maximal dose of the antip sychotic agent when it is administered alone. 54. The pharmaceutical composition of claim 52, wherein the second amount is less than an efficacious dose of the antipsychotic agent when it is administered alone. 55. The pharmaceutical composition of claim 52, wherein the 5-HT2A inverse agonist or antagonist is the compound of formula (I): coO (I) 46. A method of reducing or preventing increased serum glucose associated with administration of an antipsychotic CH agent, comprising co-administering a 5-HT2A inverse ago nist or antagonist with the antipsychotic agent to a subject at risk of or Suffering from increased serum glucose associated with administration of an antipsychotic agent. 47. The method of claim 46, wherein the 5-HT2A inverse H agonist or antagonist is the compound of formula (I): N N (I) O CH N 56. The pharmaceutical composition of claim 55, wherein the antipsychotic agent is risperidone. 57. A package, comprising: a first amount of a 5-HT2A inverse agonist or antagonist; and H N N instructions for administering the first amount of the 5-HT2A inverse agonist or antagonist and a second amount of an antipsychotic agent, wherein the first and O second amounts are such that an efficacious antipsy chotic effect is achieved faster than when the antipsy 48. The method of claim 46, wherein the antipsychotic chotic agent is administered alone at an efficacious dose. agent is risperidone. 58. The package of claim 57, wherein the second amount is 49. A method of reducing or preventing increased serum less than a maximal dose of the antipsychotic agent when it is glucose and reducing or preventing weight gain associated administered alone. with administration of an antipsychotic agent, comprising 59. The package of claim 57, wherein the second amount is co-administering a 5-HT2A inverse agonist or antagonist less than an efficacious dose of the antipsychotic agent when with the antipsychotic agent to a Subject at risk of or Suffering if is administered alone. from increased serum glucose and weight gain associated 60. The package of claim 57, wherein the 5-HT2A inverse with administration of an antipsychotic agent. agonist or antagonist is the compound of formula (I): 50. The method of claim 49, wherein the 5-HT2A inverse agonist or antagonist is the compound of formula (I): (I) (I) CH CH

O to O or to or US 2015/0231126 A1 Aug. 20, 2015 27

61. The package of claim 57, wherein the antipsychotic would not have been present at an efficacious level for sub agent is risperidone. stantially all of the period between successive dosing if first 62. A method of treatment, comprising: agent had been administered alone with the same dosing determining that a first pharmaceutical agent modulates a schedule and dosage. pharmacological property of a second pharmaceutical 68. The method of claim 62, wherein said first pharmaco agent, logical agent and said second pharmacological agent are determining that the first pharmaceutical agent has a longer administered at doses and time intervals which result in said half-life than a second pharmaceutical agent; and second pharmacological agent being present at an efficacious co-administering the first and second pharmaceutical agent level for a period of time which is longer than the period of to a patient. time which said second therapeutic agent would be present at 63. The method of claim 62, wherein the pharmacological an efficacious level if said second therapeutic agent had been property is receptor occupancy. administered alone. 64. The method of claim 62, wherein the pharmacological 69. A method of determining whether a test therapeutic property is the minimum efficacious dose of the second phar agent is a good candidate for combination therapy with a maceutical agent. therapeutic agent having a first half-life, comprising: 65. The method of claim 62, wherein the half-life of the obtaining a test therapeutic agent having a second half-life first agent is at least about 1.5 times higher than the half-life that is longer than said first half-life; and of the second agent. evaluating whether administering said test therapeutic 66. The method of claim 62, wherein the co-administration agent in combination with said therapeutic agent allows results in the second agent being present at an efficacious said therapeutic agent to be efficacious at a level at which level during at least about 50% of the time between successive it is not efficacious when administered alone. dosing of the second agent. 70. The method of claim 69, further comprising determin 67. The method of claim 62, wherein the co-administration ing whether said test therapeutic agent enhances a level of results in the second agent being present at an efficacious receptor occupancy, wherein said receptor is targeted by said level during substantially all of the tune between successive therapeutic agent. dosing of the second agent and wherein said second agent