US 2009.0053329A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0053329 A1 Peters et al. (43) Pub. Date: Feb. 26, 2009

(54) COMBINATIONS OF 5-HT2A INVERSE 61/012,771, filed on Dec. 10, 2007, provisional appli AGONSTS AND ANTAGONSTS WITH cation No. 61/026,092, filed on Feb. 4, 2008. ANTIPSYCHOTICS Publication Classification (75) Inventors: Perry Peters, San Diego, CA (US); (51) Int. Cl. David Furlano, San Diego, CA A633/00 (2006.01) (US); Daun Bahr, San Diego, CA A6II 3/445 (2006.01) (US); Daniel Van Kammen, San A 6LX 3/59 (2006.01) Diego, CA (US); Mark Brann, A6II 3/438 (2006.01) Rye, NH (US) A6IP 25/18 (2006.01) Correspondence Address: A 6LX 3L/2197 (2006.01) KNOBBE MARTENS OLSON & BEAR LLP A6II 3/54 (2006.01) 2040 MAINSTREET, FOURTEENTH FLOOR A6II 3/55 (2006.01) IRVINE, CA 92.614 (US) (52) U.S. Cl...... 424/722:514/329; 514/259.41: 514/278; 514/254.06; 514/222.2: 514/212.01 (73) Assignee: Acadia Pharmaceuticals, Inc., San Diego, CA (US) (57) ABSTRACT Combinations of 5-HT2A inverse agonists or antagonists (21) Appl. No.: 12/051,807 Such as pimavanserin with antipsychotics Such as risperidone are shown to induce a rapid onset of antipsychotic action and (22) Filed: Mar. 19, 2008 increase the number of responders when compared to therapy with the antipsychotic alone. These effects can be achieved at Related U.S. Application Data a low dose of the antipsychotic, thereby reducing the inci (60) Provisional application No. 60/895,735, filed on Mar. dence of side effects. The combinations are also effective at 19, 2007, provisional application No. 60/908,921, decreases the incidence of weight gain and increased glucose filed on Mar. 29, 2007, provisional application No. or prolactin levels caused by the antipsychotic. Patent Application Publication Feb. 26, 2009 Sheet 1 of 42 US 2009/0053329 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 No. 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 Serotonin 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 rea), anorexia, bulimia, disorders associated with alcoholism, BACKGROUND OF THE INVENTION cerebral vascular accidents, and migraine (Meltzer, Neurop 0002 1. Field of the Invention sychopharmacology, 21:106 S-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 drugs that affect serotonergic systems (Ger significant role in the functioning of the mammalian body. In shon, 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. Ne 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 2009/0053329 A1 Feb. 26, 2009

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., dystonic 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). Drug 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 medication 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 monoaminergic 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 dopamine 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 for 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 nists are therefore good candidates for treating psychosis function, orgastic dysfunction, lassitude, increased without 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, paraesthesia, 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, migrain, 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 2009/0053329 A1 Feb. 26, 2009 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. 0024. Another embodiment described herein includes a myocarditis, abnormal accommodation, Xerophthalmia, method of increasing patient compliance during antipsy diplopia, eye pain, blepharitis, photopsia, photophobia, chotic therapy, comprising co-administering a 5-HT2A abnormal lacrimation, hyponatremia, creatine phosphoki inverse agonist or antagonist with an antipsychotic agent, nase increase, thirst, weight decrease, decreased serum iron, wherein the doses of co-administration are such that patient cachexia, dehydration, hypokalemia, hypoproteinemia, compliance is increased as compared to compliance when hyperphosphatemia, hypertrigylceridemia, hyperuricemia, administering an efficacious dose of the antipsychotic agent hypoglycemia, polyuria, polydipsia, hemturia, dysuria, uri alone. nary retention, cystitis, renal insufficiency, arthrosis, Synos 0025. Another embodiment described herein includes a tosis, bursitis, arthritis, menorrhagia, dry vagina, nonpeurp method of reducing or preventing increased serum glucose eral lactation, amenorrhea, female breast pain, leukorrhea, associated with administration of an antipsychotic agent, mastitis, dysmenorrhea, female perineal pain, intermenstrual comprising co-administering a 5-HT2A inverse agonist or bleeding, vaginal hemorrhage, increased SGOT, increased antagonist with the antipsychotic agent to a subject at risk of SGPT. cholestatic hepatitis, cholecystitis, choleithiasis, hepa or Suffering from increased serum glucose associated with titis, hepatocellular damage, epistaxis, Superficial phlebitis, administration of an antipsychotic agent. thromboplebitis, thrombocytopenia, tinnitus, hyperacusis, 0026. Another embodiment described herein includes a decreased hearing, anemia, hypochromic anemia, nor method of reducing or preventing increased serum glucose mocytic anemia, granulocytopenia, leukocytosis, lymphad and reducing or preventing weight gain associated with enopathy, leucopenia, Pelger-Huet anomaly, gynecomastia, administration of an antipsychotic agent, comprising co-ad male breast pain, antiduretic hormone disorder, bitter taste, ministering a 5-HT2A inverse agonist or antagonist with the micturition disturbances, oculogyric crisis, abnormal gait, antipsychotic agent to a Subject at risk of or Suffering from involuntary muscle contraction, and increased injury. increased serum glucose and weight gain associated with 0019. In some embodiments, the condition is psychosis administration of an antipsychotic agent. 0027. Another embodiment disclosed herein includes a and the efficacious effect is an antipsychotic effect. In some pharmaceutical composition that includes a first amount of a embodiments, the psychosis is associated with Schizophre 5-HT2A inverse agonist orantagonistanda second amount of nia. In some embodiments, the psychosis is acute psychotic an antipsychotic agent, wherein the first and second amounts exacerbation. In some embodiments, the condition amenable are Such that when the composition is administered, an effi to treatment is selected from the group consisting of Schizo cacious antipsychotic effect is achieved faster than when the phrenia, bipolar disorder, agitation, psychosis, behavioral antipsychotic agent is administered alone at an efficacious disturbances in Alzheimer's disease, depression with psy dose. In some embodiments, the second amount is less than a chotic features or bipolar manifestations, obsessive compul maximal dose of the antipsychotic agent when it is adminis sive disorder, post traumatic stress syndrome, anxiety, per tered alone. In some embodiments, the second amount is less Sonality disorders (borderline and Schizotypal), dementia, than an efficacious dose of the antipsychotic agent when it is dementia with agitation, dementia in the elderly, Tourette's administered alone. syndrome, restless leg syndrome, insomnia, Social anxiety 0028. Another embodiment disclosed herein includes a disorder, dysthymia, ADHD, and autism. package that includes a first amount of a 5-HT2A inverse 0020. Another embodiment described herein includes a agonist or antagonist and instructions for administering the method of inducing a rapid onset of an antipsychotic effect, first amount of the 5-HT2A inverse agonist orantagonist and comprising co-administering a 5-HT2A inverse agonist or a second amount of an antipsychotic agent, wherein the first antagonist and an antipsychotic agent to a Subject Suffering and second amounts are such that an efficacious antipsychotic from psychosis Such that there is a rapid onset of antipsy effect is achieved faster than when the antipsychotic agent is chotic effect. 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 antidepressant 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 typical antipsychotic. 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 haloperidol. In some embodiments, the antipsychotic agent is US 2009/0053329 A1 Feb. 26, 2009 selected from the group consisting of a phenothiazine, a phe nylbutylpiperidine, a dibenzapine, a benzisoxidil, and a salt -continued of lithium. In some embodiments, the phenothiazine is F selected from the group consisting of chlorpromazine (Thora zine(R), mesoridazine (Serentil(R), prochlorperazine (Com pazine(R), thioridazine (Mellaril), Fluphenazine (Prolixin R), Perphenazine (Trilafon(R), and Trifluoperazine (Stelazine(R). In Some embodiments, the phenylbutylpiperidine is pimozide (Orap(R). In some embodiments, the dibenzapine is selected from the group consisting of clozapine (CloZaril(R), loxapine (Loxitane(R), olanzapine (ZyprexaR), and quetiapine (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 agent is selected from the group consisting of Aripiprazole 0033. In still other embodiments, the 5-HT2A inverseago (Abilify(R), Etrafon R, Droperidol (Inapsine(R). Thioridazine nist or antagonist is selected from the group consisting of (MellarilR). Thiothixene (Navane(R). Promethazine (Phener Adatanserin, Altanserin, Benanserin, Blonanserin, gan.R.), Metoclopramide (ReglanR), Chlorprothixene (Tarac Butanserin, Cinanserin, Eplivanserin, Fananserin, Fli tan.R.), Triavil(R), Molindone (Moban(R), Sertindole (Ser banserin, Glemanserin, Iferanserin, Ketanserin, Lidanserin, lect(R), Droperidol, Amisulpride (SolianR), Melperone, Mianserin, Pelanserin, Pruvanserin, Ritanserin, Seganserin, Paliperidone (InvegaR), and Tetrabenazine. and Tropanserin. 0030. Another embodiment described herein includes a 0034. In some of any of the above-mentioned methods, the method of reducing or preventing hyperprolactinemia caused administration is to a human less than eighteen years of age. by administration of risperidone, comprising co-administer 0035 Another embodiment described herein includes a ing a 5-HT2A inverse agonist or antagonist with less than 6 method of treatment that includes determining that a first mg per day of risperidone to a subject at risk of or Suffering pharmaceutical agent modulates a pharmacological property from hyperprolactinemia associated with administration of of a second pharmaceutical agent, determining that the first risperidone. pharmaceutical agent has a longer half-life than a second pharmaceutical agent, and co-administering the first and sec 0031. In some of any of the above-mentioned embodi ond pharmaceutical agent to a patient. In some embodiments, ments, the 5-HT2A inverse agonist or antagonist is the com the pharmacological property is receptor occupancy. In some pound of formula (I): embodiments, the pharmacological property is the minimum efficacious dose of the second pharmaceutical agent. In some embodiments, the half-life of the first agent is at least about (I) 1.5 times higher than the half-life of the secondagent. In some CH3 embodiments, the co-administration results in the second 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 - C - 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 co agent had been administered alone with the same dosing schedule and dosage. In some embodiments, the first phar 0032. In other embodiments, the 5-HT2A inverse agonist macological agent and said second pharmacological agent are or antagonist is a compound selected from the group consist administered at doses and time intervals which result in said ing of second pharmacological agent being present at an efficacious level for a period of time which is longer than the period 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 embodiments include determining whether said test thera US 2009/0053329 A1 Feb. 26, 2009 peutic agent enhances a level of receptor occupancy, wherein 0054 FIG. 13B is a graph depicting an isobologram that said receptor is targeted by said therapeutic agent. demonstrates Synergism upon administration of haloperidol in combination with pimavanserin. BRIEF DESCRIPTION OF THE DRAWINGS 0055 FIG. 14A is a graph depicting dose response curves for administration to mice of pimavanserin, risperidone, or 0037 FIG. 1A is a graph depicting the drug level and pimavanserin in combination with risperidone in a dizo therapeutic window for single agent administration. cilpine-induced hyperlocomotor assay. 0038 FIG. 1B is a graph depicting the drug level and 0056 FIG. 14B is a graph depicting an isobologram that therapeutic window for co-administration of two drugs hav demonstrates Synergism upon administration of risperidone ing similar half lives. in combination with pimavanserin. 0039 FIG. 1C is a graph depicting the drug level and 0057 FIG. 15A is graph illustrating the distance traveled therapeutic window for co-administration of two drugs have by mice in an amphetamine-induced hyperlocomotor assay different half lives. upon administration of pimavanserin, aripiprazole, or pima 0040 FIG. 2 is a graph depicting change in PANSS score Vanserin in combination with aripiprazole. upon administration of risperidone and haloperidol alone and 0.058 FIG. 15B is a graph illustrating dose response in combination with pimavanserin. curves for administration to mice of pimavanserin, aripipra 0041 FIGS. 3A and 3B are bar graphs depicting the per Zole, or pimavanserin in combination with aripiprazole in an cent of responders to therapy with risperidone and haloperi amphetamine-induced hyperlocomotor assay. dol alone and in combination with pimavanserin at Day 15 0059 FIG. 16A is graph illustrating the distance traveled and Day 43, respectively. by mice in an amphetamine-induced hyperlocomotor assay 0042 FIGS. 4A and 4B are graphs depicting change in upon administration of pimavanserin, quetiapine, or pima PANSS positive and negative scales, respectively, upon Vanserin in combination with quetiapine. administration of risperidone and haloperidol alone and in 0060 FIG. 16B is a graph illustrating dose response combination with pimavanserin. curves for administration to mice of pimavanserin, quetiap 0043 FIGS. 5A and 5B are graphs depicting change in ine, or pimavanserin in combination with quetiapine in an PANSS psychopathology and cognition scales, respectively, amphetamine-induced hyperlocomotor assay. upon administration of risperidone and haloperidol alone and in combination with pimavanserin. 0061 FIG. 17 is a graph depicting an isobologram that 0044 FIG. 6 is a graph depicting change in the CGI demonstrates additivity upon administration of quetiapine in severity Scale upon administration of risperidone and halo combination with pimavanserin. peridol alone and in combination with pimavanserin. 0062 FIG. 18 is a bar graph depicting percent novel object 0045 FIG. 7A is a bar graph depicting the percent of recognition upon administration of vehicle, pimavanserin, Subjects experiencing weight gain upon administration of risperidone, olanzapine, and combinations of pimavanserin risperidone and haloperidol alone and in combination with with risperidone or olanzapine in a novel object recognition pimavanserin. assay. 0063 FIG. 19 is a graph depicting working memory errors 0046 FIG. 7B is a bar graph depicting the mean weight after repeated trials upon administration of vehicle, risperi gain in Subjects upon administration of risperidone and halo done, pimavanserin, and combinations of risperidone with peridol alone and in combination with pimavanserin. pimavanserin in a radial arm maze in vivo mouse model of 0047 FIGS. 8A and 8B are graphs depicting change in cognition. prolactin levels in males and females, respectively, upon administration of risperidone and haloperidol alone and in 0064 FIG. 20A is a graph depicting serum prolactin levels combination with pimavanserin. upon administration of risperidone, haloperidol, or pimavan 0048 FIG. 9 is a bar graph depicting glucose levels upon S1. administration of risperidone alone and in combination with 0065 FIG. 20B is a bar graph depicting serum prolactin pimavanserin. levels upon administration of pimavanserin in combination 0049 FIG. 10 is a graph depicting the percent of respond with risperidone or haloperidol. ers to therapy with risperidone or haloperidol, alone or in 0.066 FIGS. 21A and 21B depict dose response curves for combination with pimavanserin. haloperidol- and risperidone-induced catalepsy in rats, 0050 FIG. 11 is a graph depicting the percent of respond respectively, upon administration of pimavanserin. ers to therapy with risperidone alone or in combination with 0067 FIG. 22 is a graph depicting mean changes in pro pimavanserin. lactin levels upon administration of risperidone alone and in 0051 FIG. 12A is graph depicting the distance traveled by combination with pimavanserin. mice in an amphetamine-induced hyperlocomotor assay upon 0068 FIG. 23 is a graph depicting plasma concentration of administration of pimavanserin, haloperidol, orpimavanserin risperidone and pimavanserin upon daily individual adminis in combination with haloperidol. tration. 0052 FIG.12B is a graph depicting dose response curves 0069 FIG. 24 is a graph depicting 5-HT2A and D2 recep for administration to mice of pimavanserin, haloperidol, or toroccupancy upon daily individual administration of risperi pimavanserin in combination with haloperidol in an amphet done and pimavanserin. amine-induced hyperlocomotor assay. (0070 FIG.25 is a graph depicting 5-HT2A and D2 recep 0053 FIG. 13A is a graph depicting dose response curves tor occupancy upon daily administration of pimavanserin in for administration to mice of pimavanserin, haloperidol, or combination with 1 mg of risperidone. pimavanserin in combination with haloperidol in a dizo (0071 FIGS. 26A and 26B are graphs depicting 5-HT2A cilpine-induced hyperlocomotor assay. and D2 receptor occupancy upon administration of 3 mg US 2009/0053329 A1 Feb. 26, 2009

risperidone twice daily alone (FIG. 26A) and in combination 0079. In some embodiments, use of the 5-HT2A inverse (FIG. 26B) with pimavanserin excluding the contribution agonist or antagonist allows the dose of the antipsychotic from paliperidone. agent to be reduced. This reduction results in an elimination 0072 FIGS. 27A and 27B are graphs depicting 5-HT2A or reduction in the severity of side effects caused by the and D2 receptor occupancy for paliperidone upon adminis antipsychotic agent. In addition, in some embodiments, tration of 3 mg risperidone twice daily alone (FIG. 27A) and reduction of the dosage of the antipsychotic agent allows the in combination (FIG. 27B) with pimavanserin. beneficial regional modulation of D2 antagonism described 0073 FIGS. 28A and 28B are graphs depicting 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 from paliperidone. then the regional modulation of D2 antagonism described 0074 FIGS. 29A and 29B are graphs depicting 5-HT2A above will not have a significant efficacious effect. 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 alone (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 alone (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, paraesthesia, aphasia, hypoesthesia, tongue in brain regions associated with motoric control or cognitive paralysis, leg cramps, torticollis, hypotonia, coma, migrain, 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, gastroeophageal 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 US 2009/0053329 A1 Feb. 26, 2009

rimation, hyponatremia, creatine phosphokinase increase, 70%, 80%, 90%, 100%, 110%, 130%, 150%, 200%, 300%, thirst, weight decrease, decreased serum iron, cachexia, 400%, or 500% when compared to administration of the dehydration, hypokalemia, hypoproteinemia, hyperphos antipsychotic agent alone at an efficacious dose. In some phatemia, hypertrigylceridemia, hyperuricemia, hypoglyce embodiments, the specified period of time is two weeks. mia, polyuria, polydipsia, hemturia, dysuria, urinary reten 0084. In various embodiments, the co-administration of tion, cystitis, renal insufficiency, arthrosis, Synostosis, the 5-HT2A inverse agonist or antagonist with the antipsy bursitis, arthritis, menorrhagia, dry vagina, nonpeurperallac chotic agent is used to treat, prevent, or ameliorate the Symp tation, amenorrhea, female breast pain, leukorrhea, mastitis, toms of a neuropsychiatric 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, antiduretic 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 posttraumatic ment, side effect is associated with administration of the stress disorder), Suicidal tendency, bipolar disorder, sleep antipsychotic to a child under 18. In one embodiment, the side disorder (including sleep maintenance insomnia, chronic effect in the child is selected from psychosis, schizophrenia, insomnia, transient insomnia, and periodic limb movements pervasive developmental disorder, autism, Tourette's Syn during sleep (PLMS)), addiction (including drug or alcohol drome, conduct disorder, aggression, attention and hyperac addiction, opioid addiction, and nicotine addiction), attention tivity difficulties (e.g., ADD, ADHD). In some embodiments, deficit hyperactivity disorder (ADHD), post traumatic stress the side effects of weight gain, heart rhythm problems, and disorder (PTSD), Tourette's syndrome, anxiety (including diabetes are more severe in children. general anxiety disorder (GAD)), autism, Down's syndrome, 0081. In some embodiments, due to decreased side effects, learning disorders, psychosomatic disorders, alcohol with the co-administration described herein can be used to drawal, epilepsy, pain (including chronic pain, neuropathic increase patient compliance during antipsychotic therapy. pain, inflammatory pain, diabetic peripheral neuropathy, 0082 In some embodiments, the antipsychotic agent is fibromyalgia, postherpetic neuralgia, and reflex sympathetic administered at a sub-maximal level. In various such embodi dystrophy), disorders associated with hypoglutamatergia (in ments, the dosage of the antipsychotic agent is less than about cluding schizophrenia, childhood autism, and dementia), and 75%, 60%, 50%, 40%, 30%, 20%, or 10% of the maximal 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 the 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 500% 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 US 2009/0053329 A1 Feb. 26, 2009 dysfunction (including female sexual dysfunction, female 0091. Many antipsychotic agents also cause weight gain. sexual arousal dysfunction, hypoactive sexual desire disor In some embodiments, the co-administration of the 5-HT2A der, decreased libido, pain, aversion, female orgasmic disor inverse agonist or antagonist with the antipsychotic agent is der, and ejaculatory problems), low male fertility, low sperm used to prevent or reduce increased weight gain associated with administration of the antipsychotic agent. motility, hair loss or thinning, incontinence, hemorrhoids, 0092. In some embodiments, the 5-HT2A inverse agonist migraine, hypertension, thrombosis (including thrombosis orantagonist is selective for the 5-HT2A receptor. By “selec associated with myocardial infarction, stroke, idiopathic tive it is meant that an amount of the compound Sufficient to thrombocytopenic purpura, thrombotic thrombocytopenic effect the desired response from the 5-HT2A receptor has purpura, and peripheral vascular disease), abnormal hor little or no effect upon the activity of other certain receptor monal activity (such as abnormal levels of ACTH, corticos types, subtypes, classes, or Subclasses. In some embodi terone, rennin, or prolactin), hormonal disorders (including ments, the 5-HT2A inverse agonist or antagonist does not Cushing's disease. Addison's disease, and hyperprolactine interact strongly with other serotonin receptors (5-HT1A, mia), a pituitary tumor (including a prolactinoma), a side 1B, 1D, 1E, 1 F.2B, 2C, 4A, 6, and 7) at concentrations where effect associated with a pituitary tumor (including hyperpro the signaling of the 5-HT2A receptor is strongly or com lactinemia, infertility, changes in menstruation, amenorrhea, pletely inhibited. In some embodiments, the 5-HT2A inverse galactorrhea, loss of libido, vaginal dryness, osteoporosis, agonist or antagonist is selective with respect to other impotence, headache, blindness, and double vision), vasos monoamine-binding receptors, such as the dopaminergic, pasm, ischemia, cardiac arrythmias, cardiac insufficiency, histaminergic, adrenergic and muscarinic receptors. In some asthma, emphysema, or appetite disorders. embodiments, the 5-HT2A inverse agonist or antagonist has 0088. In some embodiments, the co-administration is used little or no activity at D2 receptors. to treat, prevent, or ameliorate psychosis. Functional causes 0093. In various embodiments, the 5-HT2A inverse ago of the psychosis may include Schizophrenia, Parkinson's dis nist or antagonist is selected from the group consisting of ease, Alzheimer's disease, bipolar disorder, severe clinical Adatanserin Hydrochloride. Altanserin Tartrate, Benanserin depression, severe psychosocial stress, sleep deprivation, Hydrochloride, Blonanserin, Butanserin, Cinanserin Hydro neurological disorders including brain tumor, dementia with chloride, Eplivanserin, Fananserin, Flibanserin, Gle Lewy bodies, multiple Sclerosis, and sarcoidosis, electrolyte manserin, Iferanserin, Ketanserin, Lidanserin, Mianserin disorders including hypocalcemia, hypernatremia, hyonatre Hydrochloride, Pelanserin Hydrochloride, Pruvanserin, mia, hyopkalemia, hypomagnesemia, hypermagnesemia, Ritanserin, Seganserin, Tropanserin Hydrochloride, Iloperi hypercalcemia, hypophosphatemia, and hypoglycemia, done, Sertindole, EMR-62218, Org-5222, Zotepine, asenap lupus, AIDS, leprosy, malaria, flu, mumps, psychoactive drug ine, Ocaperidone, APD125, and AVE8488. intoxication or withdrawal including alcohol, barbiturates, 0094. In some embodiments, the 5-HT2A inverse agonist benzodizepeines, anticholinergics, atropine, Scopolamine, or antagonist is selected from a compound disclosed in U.S. Jimson weed, antihistamines, cocaine, amphetamines, and Pat. No. 6,756,393; 6,911,452; or 6,358,698 or U.S. Applica hallucinogens including cannabis, LSD, psilocybin, mesca tion Publication No. 2004-0106600, all of which are incor line, MDMA, and PCP. Psychosis may include symptoms porated herein by reference in their entirety. In some embodi Such as delusions, hallucinations, disorganized speech, dis ments, the 5-HT2A inverse agonist or antagonist is selected organized behavior, gross distortion of reality, impaired men from one of the following structures or prodrugs, metabolites, tal capacity, impaired affective response, fluctuating level of hydrates, Solvates, polymorphs, and pharmaceutically consciousness, poor motor co-ordination, inability to per acceptable salts thereof: form simplemental tasks, disorientation as to person, place or F time, confusion, or memory impairment. In one embodiment, the patient is experiencing acute exacerbation of psychosis. 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 N embodiment, the patient has exhibited a prior response to antipsychotic therapy. In one embodiment, the patient exhib its a moderate degree of psychopathology. 4-M / 0089. In one embodiment, the co-administration is used to treat depression. In one embodiment, the co-administration F results in a rapid onset of antidepressant activity as compared to the onset of activity observed with typical antidepressants (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 N levels. It has been surprisingly discovered that combination of N 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 Sr. antipsychotic agent is used to prevent or reduce increased 0095. In one embodiment, the 5-HT2A inverse agonist or serum glucose associated with administration of the antipsy antagonist is pimavanserin or prodrugs, metabolites, chotic agent. hydrates, Solvates, polymorphs, and pharmaceutically US 2009/0053329 A1 Feb. 26, 2009

acceptable salts thereof. Pimavanserin, which is also known the peptide is metabolized to reveal the active moiety. Con 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 CH3 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 , - C -l 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 organic acid such as aliphatic or aromatic carboxylic or Sul co 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, citrate, 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 CARBAMIDE AND THEIR PREPARATION, which is amine, and salts with amino acids such as arginine, lysine, 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 E 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-METHYLPIPERIDIN-4-YL)- basic, that is, either acidic or neutral excipients. N'-(4-(2-METHYLPROPYLOXY)PHENYLMETHYL) 0101 Pimavanserin exhibits activity at monoamine recep CARBAMIDE 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 2007-0264330, 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 are 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 Ziprasidone 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 5HT 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 US 2009/0053329 A1 Feb. 26, 2009 antagonist MK-801. The compound was effective in these 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 O Schizophrenics, pimavanserin at doses of 1 and 3 mg/kg SC potently reversed the gating deficit induced by DOI. Pima o1 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 KOH MeOH-HO gests it will be effective as an antipsychotic agent without the -es 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 u? fication in temperature, Solvent, reagents, etc. (IV) 0104. The first step of the synthesis, illustrated below, is conducted in the presence of acetic acid, NaBHCN, and 0107 The compound of formula (V) is heated to reflux methanol to produce the compound of formula (II): with diphenylphosphonyl azide (DPPA) and a proton sponge in tetrahydrofuran (THF) to produce the compound of for mula (VI): O NaBHCN N HOAc NCO MeOH OH -- He

DPPA Proton Sponge THF O F reflux

N F u? u? OUI (V) (VI) 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

CHCl2 O F -- -- O 1. O 1. i-BuBr NH 1. K2CO3 DMF (II) (VI) -- 80° C. O N OH F - (III) H (IV) N 0106 The compound of formula (IV) can be converted to O the compound of formula (V) by reaction with potassium (I) hydride in methanol/water: US 2009/0053329 A1 Feb. 26, 2009

0109) Non-limiting examples of suitable antipsychotic aliphatic alcohols, 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), prochlorperazine (Compazine(R). lose, and the like may be used as excipients; magnesium thioridazine (Mellaril), Fluphenazine (Prolixin R), Perphena Stearate, talc, hardened oil and the like may be used as zine (TrilafonR), and Trifluoperazine (Stelazine(R). In some Smoothing agents; coconut oil, olive oil, sesame oil, peanut embodiments, the phenylbutylpiperidine is selected from the oil, Soya may be used as Suspension agents or lubricants; group consisting of haloperidol (Haldol(R) and pimozide cellulose acetate phthalate as a derivative of a carbohydrate (Orap(R). In some embodiments, the dibenzapine is selected Such as cellulose or Sugar, or methylacetate-methacrylate from the group consisting of clozapine (CloZaril(R), loxapine copolymer as a derivative of polyvinyl may be used as Sus (Loxitane(R), olanzapine (ZyprexaR), and quetiapine (Sero pension agents; and plasticizers such as ester phthalates and quel(R). In some embodiments, the benzisoxidil is selected the like may be 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 cells 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 Sertindole (Serlect(R), Droperidol, Amisulpride (Solian(R), pound. Salts dissolved in buffered solutions are utilized as Melperone, Paliperidone (InvegaR), and Tetrabenazine. In diluents in the art. One commonly used buffered solution is Some embodiments, the antipsychotic is a D2 antagonist. In phosphate buffered 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 2009/0053329 A1 Feb. 26, 2009 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. Dyestuffs 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.2. 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 insulator 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 (Shedden et al., Clin. Then, 23(3):440-50 (2001)) or a patient to be treated. Pharmaceutical preparations for oral hydrogels (Mayer et al., Opthalmologica, 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. Ocil. 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 hydroxypropylmethyl-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 arabic, 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 2009/0053329 A1 Feb. 26, 2009

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. Many 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. polyvinyl drug. As illustrated for some drugs with a narrow therapeutic pyrrolidone; and other Sugars or polysaccharides may substi window, even the optimal dose results in plasma levels out tute 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 receptor antagonist 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 2009/0053329 A1 Feb. 26, 2009 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 discretion of each principal investigator (PI), completed the wherein the first agent has a higher half-life than the second trial as outpatients. Subjects were evaluated at Screening, agent. In some embodiments, the half-life of the first agent is after a drug-free lead-in period (Baseline Day -1), and peri at least about 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, odically thereafter by the PANSS, the Clinical Global Impres 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, sion Scale-Severity (CGI-S), the Calgary Depression Scale 4.0, or more than 4.0 times higher than the half-life of the for Schizophrenia (CDSS), the Simpson and Angus Scale second agent. In some embodiments, the first agent modu (SAS), and the Barnes Akathisia Scale (BAS). lates the activity of the second agent. In some embodiments, 0140 Male and female subjects, age inclusive from 18-65, the first and second agents are selected Such that their relative with a clinical diagnosis of schizophrenia (DSM-IV 295. half-lives and the modulating effect of the first agent on the XX), are enrolled. Subjects are experiencing an acute psy second agent results in the second agent being present at an chotic exacerbation, and have at least a moderate degree of efficacious dose during at least about 50%, 60%, 70%, 80%, psychopathology (total score on the PANSS of 65 or greater), 90%, or 100% of the time between successive dosing of the and a score greater than or equal to 4 on two of the four Second 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 medications 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 Admin cept Days 1, 22 and 36), and plasma sampling for the pima istered to Schizophrenic Patients Vanserin, haloperidol, and risperidone concentrations. A final 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 2009/0053329 A1 Feb. 26, 2009 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 drug 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-severity 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) of 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. The 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 PANSS 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 depicting the percent of subjects with toward a faster onset of efficacy. Specifically, at two weeks US 2009/0053329 A1 Feb. 26, 2009 after the start of treatment, the percent responders for the 0.165 Pimavanserin did not potentiate the efficacy of haloperidol/pimavanserin combination were higher than for haloperidol. haloperidol alone. 0166 Low dose risperidone was significantly less effec 0158. As Table 1 demonstrates, the haloperidol/pimavan tive than the other treatments. serin combination also resulted in less weight gain than 0.167 Pimavanserin enhanced the efficacy of low dose observed when administering haloperidol alone. risperidone at all time points from week 2 on with regard to PANSS Total, POS, NEG, General, and CGI. TABLE 1. 0168 Pimavanserin/risperidone was more effective than high dose risperidone and low dose risperidone at Haloperidol Haloperidol + Pimavanserin day 15 with regard to % patients with >20% decrease in Initial mean weight (kg) 82.993 82.943 PANSS Total. Final mean weight (kg) 83.759 83.385 0.169 Pimavanserin/risperidone was as effective as Mean weight gain (kg) 0.7657 O4426 high dose risperidone, haloperidol and pimavanserin/ haloperidol at all time points, with all measures. 0159. Co-administering pimavanserin with risperidone 0170 Pimavanserin/risperidone had less % of patients also provided highly significant antipsychotic efficacy (p<0. with >7% weight gain than high dose risperidone or low 0001). Efficacy enhancement was observed when compared dose risperidone. to 2 mg of risperidone administered alone (mean change in 0171 Serum glucose and prolactin levels (PRL) were PANNS score of 23.0 vs. 16.6 points) and similar efficacy was lower in pimavanserin/risperidone than high dose ris observed when compared to 6 mg of risperidone administered peridone: PRL levels were lower in haloperidol-treated alone. Efficacy of the combination was observed for both patients compared to risperidone patients. positive and negative symptoms of psychosis. The co-admin 0.172. There was a trend to less akathesia in the pima istration resulted in improved treatment of emotional with Vanserin co-therapy groups compared to the respective drawal, lack of spontaneity and flow of conversation, abnor risperidone and haloperidol arms. mal mannerisms and posturing, motor retardation, uncooperativeness, lack of judgment and insight, poor Example 2 impulse control, and preoccupation as compared to 6 mg per day of risperidone administered alone. Combinations of Haloperidol and Risperidone with 0160 FIG. 11 is a graph depicting the percent of respond Pimavanserin for Suppressing Drug-Induced Hyper ers for those Subjects receiving risperidone, defined as those activity in Mice subjects experiencing at least a 20% reduction in PANSS 0173 Male non-Swiss albino (NSA) mice and Sprague score. The results indicate that the combination treatment Dawley (SD) rats (Harlan, San Diego, Calif.) served as sub resulted in a faster onset of efficacy. Specifically, at two weeks jects for the present investigation. Animals were housed in after the start of treatment, the percent responders for the climate-controlled rooms on a 12/12 light dark cycle with on risperidone/pimavanserin combination were higher than for lights at 0600 hr. Rats were housed in groups of two and mice risperidone alone (both the 2 mg and 6 mg doses). were housed in groups of eight. Food and water was available 0161. As Table 2 demonstrates, the risperidone/pimavan ad libitum except during experimental procedures. At the serin combination resulted in less weight gain than observed time of testing, mice weighed 20-30 g and the rats weighed when administering 6 mg of risperidone alone. The difference between 275-325 g. was approaching statistical significance (p=0.0784). 0.174 Amphetamine, dizocilpine (i.e., MK-801), and haloperidol were obtained from Sigma (St. Louis, Mo.). Ris TABLE 2 peridone was obtained from Toronto Research Chemicals 2 mg 6 mg Risperidone + (North York, ON, Canada). Pimavanserin were synthesized Risperidone Risperidone pimavanserin by ACADIA Pharmaceuticals, Inc. Drugs were administered eitherina volume of 0.1 mL per 10g body weight or of 1.0 mL Initial mean weight (kg) 80.702 79.216 79.533 per kg body weight to mice and rats, respectively. The vehicle Final mean weight (kg) 81.856 81.332 80.6OO used for amphetamine, dizocilpine, and ACP-103 was saline. Mean weight gain (kg) 1.1540 2.1162 1.0667 Amphetamine and dizocilpine were administered intraperi toneally (ip). The vehicle used for haloperidol and risperi 0162 Conclusion: The combination of low dose risperi done was 10% Tween 80 in saline unless otherwise specified. done with pimavanserin was superior to that of either low Haloperidol and risperidone were administered subcutane dose or high dose risperidone alone in terms of time of onset ously (Sc), unless otherwise noted. The doses of pimavanserin of response and percent of patients with good clinical are expressed as free-base and were administered by the sc response. The efficacy of haloperidol was not potentiated by rOute. pimavanserin, perhaps because with haloperidol alone, the 0.175 Amphetamine-induced Hyperlocomotor Activity occupancy of D2 receptors is sufficient to achieve optimal Assay: Hyperlocomotion was produced in mice by adminis outcome, whereas that of low dose risperidone alone is not. tration of amphetamine (3 mg/kg) 15 min prior to entering The advantage of using low doses of atypicals +pimavanserin motor activity chambers (AccuScan Instruments, Columbus, extends to reduced side effect burden on metabolic measures Ohio). Dose response curves were constructed for haloperi and EPS and, potentially, to a broadened efficacy. dol in the presence of vehicle or a fixed dose of pimavanserin 0163 The conclusions are summarized as follows: (0.03 mg/kg). Vehicle or haloperidol was injected 30 min 0164 Pimavanserin potentiated efficacy of low dose prior to entering activity chambers. Vehicle or pimavanserin risperidone on psychopathology while reducing side was given 30 min prior to haloperidol (i.e., 60 min prior to effects. entering activity chambers). Immediately prior to placing the US 2009/0053329 A1 Feb. 26, 2009

mice into the activity chambers, the presence of ataxia and calculated IDs value of 0.012 mg/kg (0.009-0.016; 95% CI). muscle incoordination was determined using the horizontal However, when combine with a fixed dose of pimavanserin wire test (Vanover et al., 2004). Once inside the chambers, (0.03 mg/kg, filled squares), the dose-response curve for total distance traveled (DT) in cm was determined across a 15 haloperidol was significantly shifted to the left by a factor of min session. In order to generate dose-response curves, raw approximately 10 with a calculated IDso value of 0.0013 DT data were converted to % MPI:% MPI-((DT drug or drug mg/kg (0.0005-0.0031: 95% CI). The combination of pima combination-DT amphetamine control)/(DT vehicle con vanserin and haloperidol resulted in a 9.5-fold (3.8-23.8; 95% trol-DT amphetamine control))* 100. The IDs values and the CI) shift in potency. Each data point represents a minimum n corresponding 95% CI were determined as previously men of 8. tioned. Mice had no prior exposure to the chambers and each 0180. Effects of haloperidol and pimavanserin, alone and dose combination was tested in separate groups of mice. in combination, on Suppression of dizocilpine-induced 0176) Dizocilpine-induced Hyperlocomotor Activity hyperlocomotion in mice: FIG. 13A is a graph depicting dose Assay: Hyperlocomotion was produced in mice by adminis response curves for haloperidol (open squares), pimavanserin tration of dizocilpine (0.3 mg/kg) 15 min prior to entering (filled squares), and the combination of haloperidol with motor activity chambers. Dose response curves were con pimavanserin in a 1:1 fixed dose ratio (filled circles) on the structed for haloperidol, risperidone and pimavanserin. Halo Suppression of dizocilpine-induced hyperactivity. Each data peridol or risperidone was injected 30 min prior to, and pima point represents a minimum n of 16. As expected, dizocilpine Vanserin was administered 60 min prior to entering the treatment significantly increased DT to 2227+116 cm from activity chambers. Immediately prior to placing the mice into 792+40 cm obtained in the vehicle controls. Administration the activity chambers the presence of ataxia and muscle inco of either haloperidol or pimavanserin elicited a dose-depen ordination was determined as previously described and DT dent attenuation of dizocilpine-induced hyperlocomotion was determined across a 15 min session. Raw data were achieving IDs values of 0.07 mg/kg (0.063-0.087; 95% CI) transformed to % MPI and IDs values and corresponding and 0.09 mg/kg (0.067-0.12: 95% CI), respectively. Given 95% CI were determined as previously described. Mice had that haloperidol and pimavanserin were equipotent in this no prior exposure to the chambers and each dose combination assay, a 1:1 fixed-dose ratio (haloperidol:ACP-103) was was tested in separate groups of mice. administered infractions of the approximated IDso dose com 0177. Drug-interaction Studies: Isobolographic analysis binations of 0.06+0.06 mg/kg (IDs/2=0.03+0.03 mg/kg: was used to determine the nature of the drug interaction IDs/4=0.015+0.015 mg/kg: IDs/8=0.0075+0.0075 mg/kg). between either haloperidol or risperidone and pimavanserin Co-administration of haloperidol and pimavanserin produced on Suppression of dizocilpine-induced hyperlocomotor activ a dose-dependent attenuation of hyperlocomotor activity ity. This method is based on the comparison of dose combi induced by dizocilpine achieving a % MPI of 103+6%. nations in which the doses of each individual agent are deter 0181 Isobolographic analysis conducted using the equi mined to be equi-efficacious. In this case, dose-response potent ratio and the resulting isobologram is presented in FIG. curves were generated following co-administration of either 13B. The calculated IDs (and 95% CI) values for pimavan haloperidol or risperidone with pimavanserin in a fixed dose serin and haloperidol when administered alone (open ratio based on the individual calculated IDso values. There squares) are plotted on the X- and y-axes, respectively. The fore, separate groups received: pimavanserin IDso-haloperi dashed line connecting these two points represents the line of dol or risperidone IDso: (pimavanserin IDs +haloperidol or theoretical additivity. The experimental IDs (filled circle, B) risperidone IDso)/2; (pimavanserin IDso-haloperidol or ris for the dose combination was significantly less than the theo peridone IDs)/4; and (pimavanserin IDso-haloperidol or ris retical IDso (filled square, A), indicating a synergistic inter peridone IDso)/8. Based on the dose-response curves action. The experimental IDs for the dose mixture was sig obtained for the combined agents (i.e., pimavanserin-halo nificantly less than the theoretical IDso, values of 0.04 mg/kg peridol orpimavanserin-i-risperidone), IDs value and 95% CI (0.03-0.05: 95% CI) and 0.08 mg/kg (0.68-0.93; 95% CI), for each drug combination was obtained. respectively. These results indicate that efficacy is maintained 0.178 Effects of haloperidol alone, and in combination at 50% of haloperidol dose. with pimavanserin, on Suppression of amphetamine-induced 0182 Effects of risperidone and pimavanserin, alone and hyperlocomotion in mice: FIG. 12A is graph illustrating the in combination, on Suppression of dizocilpine-induced distance traveled as a function of haloperidol dose for the hyperlocomotion in mice: FIG. 14A is a graph depicting dose various administered agents. Relative to vehicle controls response curves for risperidone (open Squares), pimavanserin (open circle), amphetamine (open triangle) significantly (filled squares), and the combination of risperidone with increases hyperlocomotor activity in mice (increased DT to pimavanserin in a 1:18 fixed dose ratio (filled circles) on the 2764+230 cm from 876+42 cm obtained in the vehicle con Suppression of dizocilpine-induced hyperactivity. Each data trols). Pimavanserin at a dose of 0.03 mg/kg (filled circle) point represents a minimumn of 16. As in the previous experi failed to Suppress hyperlocomotion produced by amphet ment, dizocilpine treatment significantly increased total DT amine. In contrast, haloperidol (open squares) dose depen to 2020-223 cm from 649-67 cm obtained in the vehicle dently attenuated hyperactivity produced by amphetamine. controls. Administration of either risperidone or pimavan However, haloperidol, when combined with a fixed dose of serin elicited a dose-dependent attenuation of dizocilpine pimavanserin (0.03 mg/kg, filled squares), demonstrated an induced hyperlocomotion achieving IDs values of 0.0045 enhanced Suppression of amphetamine-induced hyperloco mg/kg (0.003-0.006: 95% CI) and 0.09 mg/kg (0.067-0.12: motor activity. 95% CI), respectively. Given that risperidone was more 0179 The raw data contained in FIG. 12A were converted potent than pimavanserin in this assay, a 1:18 fixed-dose ratio to % MPI to generate dose-response curves depicted in FIG. (risperidone:pimavanserin) was administered in fractions of 12B. Haloperidol (open squares) produced a dose-dependent the approximated IDso dose combinations of 0.005+0.09 attenuation of hyperactivity elicited by amphetamine with a mg/kg (IDs/2=0.0025+0.045 mg/kg: IDs/4=0.00125+0. US 2009/0053329 A1 Feb. 26, 2009

0225 mg/kg: IDs/8-0.000625+0.01 125 mg/kg). Co-admin ate the actions of haloperidol via director indirect modulation istration of risperidone and pimvanserin produced a dose of evoked DA release in the NAC. Another possibility is that dependent attenuation of hyperlocomotor activity induced by 5-HT, inverse agonists may block a "pro-psychotic drive dizocilpine achieving a % MPI of 82+8%. associated with APD-induced enhanced serotonergic trans 0183) Isobolographic analysis was conducted using the mission in limbic or cortical structures. Following systemic fixed dosing ratio and the resulting isobologram is presented administration of NMDA antagonists, extracellular DA and in FIG. 14B. The calculated IDs (and 95% CI) values for 5-HT concentrations rise in the NAC, and medial prefrontal pimavanserin and risperidone when administered alone (open cortex (mPFC). High doses of atypical APDs, such as cloza squares) are plotted on the X- and y-axes, respectively. The pine and olanzapine, but not typical APDs, such as haloperi dashed line connecting these two points represents the line of dol, produce preferential increases in DA release in the mPFC theoretical additivity. The experimental IDs (filled circle, B) compared to the NAC, a property that may explain how atypi for the dose combination was significantly less than the theo cal APDS improve cognition in Schizophrenia. Regardless of retical IDso (filled square, A), indicating a synergistic inter the mechanism, these findings indicate that pimavanserin has action. The experimental IDs for the dose mixture was sig dose-sparing actions for APDS in models predictive of antip nificantly less than the theoretical IDs, values of 0.0032 sychotic action. mg/kg (0.0007-0.005895% CI) and of 0.045 mg/kg (0.035 0186. In conclusion, the above data Suggests that pima 0.054: 95% CI), respectively. These results indicate that effi Vanserin, via 5-HT2 receptor antagonism or inverse ago cacy is maintained at /3 of risperidone dose. nism, results in a significant dose-sparing effect Such that 0184 Conclusion: Pimavanserin, at a dose that does not antipsychotic efficacy can be maintained, or improved, while Suppress amphetamine-induced hyperactivity, when com concomitantly reducing the severity of unwanted side effects bined with haloperidol, produced an approximate 10-fold mediated via D receptor antagonism. The findings with ris shift in the potency of haloperidol against amphetamine peridone Suggest that the dose-sparing benefits of pimavan induced hyperactivity. Further, pimavanserin interacted Syn serin will be manifested even with those atypical APDs hav ergistically with haloperidol, and with risperidone, to reduce ing an inherently high affinity for 5-HT2 receptors. This is dizocilpine-induced hyperactivity. The supra-additive consistent with clinical findings indicating that even for those actions of pimavanserin were not achieved by simply altering APDs which have relatively high affinity for 5-HT, recep the pharmacokinetics of either haloperidol or risperidone, as tors, 5-HT, receptor blockade is not fully achieved at clini brain exposures for these agents were not significantly altered cally tolerated doses. in the presence of pimavanserin. For example, Table 3 indi cates brain levels of pimavanserin and haloperidol for various Example 3 dosages. The results indicate that full efficacy can beachieved Combinations of Aripiprazole and Quetiapine with using the combination with one half haloperidol brain con Pimavanserin for Suppressing Drug-Induced Hyper centration. The doses used in these studies are consistent with activity in Mice a 5-HT, receptor mechanism of action. These data indicate that even for compounds that possess high affinity for 5-HT 0187. The protocol described above in Example 2 was receptors, complete 5-HT, 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 triangle) significantly increases hyperlocomotor activity in Treatment Pimavanserin brain levels Haloperidol brain levels mice. Pimavanserin at a dose of 0.03 mg/kg (filled circle) conditions (nmol/kg) (nmol/kg) failed to suppress hyperlocomotion produced by amphet Pim + Veh 23 (+6) amine. In contrast, aripiprazole (open squares) dose depen Veh + Hal (0.003) &10 dently attenuated hyperactivity produced by amphetamine. Veh + Hal (0.01) 43 (+5) 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) motor activity. Pim + Hal (0.01) 14 (+6) 45 (+7) 0188 The raw data contained in FIG. 15A were converted to % MPI to generate dose-response curves depicted in FIG. 0185. The mechanism by which 5-HT, receptor blockade 15B. Aripiprazole (open squares) produced a dose-dependent enhances the action of antipsychotics (APDs) in these models attenuation of hyperactivity elicited by amphetamine. How is unknown, however, microdialysis and other studies suggest ever, when combined with a fixed dose of pimavanserin (0.03 several possibilities. While not being bound by any particular mg/kg, filled squares), the dose-response curve for aripipra theory, one possibility is that 5-HT, inverse agonists may Zole was significantly shifted to the left. have regionally specific effects on dopamine (DA) transmis 0189 FIG. 16A is graph illustrating the distance traveled sion. Previous studies have shown that DOI increases DA as a function of quetiapine dose for the various administered release and potentiates amphetamine-induced DA release in agents. Relative to vehicle controls (open circle), amphet the nuclear accumbens (NAC), Suggesting that 5-HT, recep amine (open triangle) significantly increases hyperlocomotor tor inverse agonists are more apt to modulate evoked, rather activity in mice. Pimavanserin at a dose of 0.03 mg/kg (filled than basal, DA release. Haloperidol, which potently inhibits circle) failed to Suppress hyperlocomotion produced by amphetamine hyperactivity, has been shown to paradoxically amphetamine. In contrast, quetiapine (open squares) dose increase DA release in the NAC, an effect blocked by pima dependently attenuated hyperactivity produced by amphet Vanserin. These data Suggest that pimavanserin may potenti amine. However, quetiapine, when combined with a fixed US 2009/0053329 A1 Feb. 26, 2009 dose of pimavanserin (0.03 mg/kg, filled squares), demon serum for analysis. Serum prolactin levels were quantified strated an enhanced suppression of amphetamine-induced using a commercially available enzyme immunoassay kit hyperlocomotor activity. (ALPCO Diagnostics, Windham, N.H.). 0190. The raw data contained in FIG.16A were converted 0196. In order to explore the potential interaction between to % MPI to generate dose-response curves depicted in FIG. haloperidol or risperidone and pimavanserin on serum pro 16B. Quetiapine (open squares) produced a dose-dependent lactin levels, rats were dosed sc with either vehicle or various attenuation of hyperactivity elicited by amphetamine. How doses of pimavanserin, then 30 min later, dosed ip with either ever, when combined with a fixed dose of pimavanserin (0.03 vehicle or a fixed dose of haloperidol or risperidone. Blood mg/kg, filled squares), the dose-response curve forquetiapine samples were collected 30 min following vehicle, haloperidol was shifted to the left. or risperidone administration (i.e., 60 min following vehicle 0191 The effects of quetiapine and pimavanserin, alone or pimavanserin administration). The time point for sample and in combination, on Suppression of dizocilpine-induced collection was chosen based on our work and that of others hyperlocomotion in mice was also evaluated. Isobolographic (Liegeois et al., 2002b), which show that 30 minappears to be analysis was conducted and the resulting isobologram is pre the time at which peak prolactin levels can be detected fol sented in FIG. 17. The calculated IDs (and 95% CI) values lowing risperidone or haloperidol treatment, respectively. for pimavanserin and quetiapine when administered alone The fixed doses of haloperidol (0.1 mg/kg) and risperidone (open Squares) are plotted on the X- and y-axes, respectively. (0.01 mg/kg) were chosen since they elicited statistically The dashed line connecting these two points represents the significant and reproducible, but Sub-maximal, increases in line of theoretical additivity. The experimental IDs (filled prolactin, thus allowing for the detection of potential square, B) for the dose combination was not significantly increases as well as decreases. different than the theoretical IDs (filled circle, A), indicating 0.197 Effects of haloperidol and risperidone alone, and in an additive interaction. combination with pimavanserin, on serum prolactin levels in rats: FIG. 20A is a graph depicting the dose response of Example 4 prolactin levels obtained in rats following various doses of Use of Pimavanserin for Reversing Cognitive risperidone (filled squares), haloperidol (open squares) and Impairment in Mice Administered Anti-Psychotics pimavanserin (filled circles). Serum prolactin levels obtained in vehicle-treated controls were 24+3 ng/mL and 31+3 ng/mL 0.192 Various antipsychotics were administered alone or after 30 min and 60 min, respectively. As expected, 60 min in combination with pimavanserinto mice in an in vivo mouse following haloperidol treatment rats demonstrated a dose model of cognition. Compounds were administered to mice at related increase in serum prolactin levels as compared to one hour post-training (a time-point at which animals nor vehicle controls. Similarly, 30 min following risperidone mally behaviorally discriminate between novel and familiar treatment, a dose-dependent increase in serum prolactin lev objects) and two hours post-training (a time-point at which els was observed. In contrast, pimavanserin treatment, up to 3 these animals normally no longer discrimate between mg/kg, did not significantly elevate serum prolactin levels as objects). compared to vehicle-treated controls. Rather, rats treated with 0193 FIG. 18 is a bar graph of percent novel object rec pimavanserin demonstrated a significant reduction in serum ognition upon administration of vehicle, pimavanserin (0.3 prolactin concentrations, as the values obtained were 31+3 mg/kg), risperidone, olanzapine, and combinations of pima ng/mL and 15-0 ng/mL after vehicle and 3 mg/kg pimavan Vanserin with risperidone or olanzapine. The results indicate serin, respectively. Allrats treated with 3 mg/kg pimavanserin that pimavanserin reverses novel object recognition impair had serum prolactin concentrations below the limit of detec ment caused by risperidone and olanzapine. tion; hence a value of 15 ng/mL was assigned. 0194 Combinations of pimavanserin and risperidone (0198 FIG. 20B depicts the serum prolactin levels were also evaluated in a radial arm maze in vivo mouse model obtained in rats following fixed doses of risperidone (0.01 of cognition. FIG. 19 is a graph indicating working memory mg/kg, filled bars) or haloperidol (0.1 mg/kg, open bars) in errors after repeated trials upon administration of vehicle, the presence of vehicle or various doses of pimavanserin. risperidone, pimavanserin (1 mg/kg), and combination of Each data point represents a minimum n of 12. ** denotes risperidone with pimavanserin. The results indicated that p<0.01: * denotes p-0.05. The dose of haloperidol signifi pimavanserin improved the cognitive deficit induced by ris cantly increased serum prolactin levels from 313 ng/mL to peridone. 102-12 ng/mL. Similarly, risperidone significantly increased serum prolactin levels from 24+3 ng/mL to 102+12 ng/mL. Example 5 However, in the presence of pimavanserin, at doses consistent with 5-HT2 receptor blockade, the magnitude of prolactine Attenuation of Other Side Effects when Pimavan mia induced by either haloperidol or risperidone was signifi serin is Co-Administered with Antipsychotics cantly attenuated. 0.195 Prolactin Assay: Dose response curves were gener 0199 Catalepsy Assessment: Rats were positioned with ated for haloperidol, risperidone and pimavanserin on serum their forepaws on a horizontalbar (diameter 10 mm); elevated prolactin levels. Rats were dosed ip with vehicle (100% dim 10 cm above the bench top, and the duration of the cataleptic ethyl sulfoxide), haloperidol or risperidone, while pimavan bout was recorded up to a maximum catalepsy value of 120 serin or vehicle (Saline) was given Sc. Blood samples were sec. Catalepsy values (CVs) were obtained at 30 and 60 min collected 30 min following vehicle, haloperidol or risperi following ip administration risperidone or haloperidol. done administration or 60 min after pimavanserin adminis respectively. Doses of pimavanserin were administered sc 60 tration. Rats were deeply anesthetized with isoflurane and min prior to either haloperidol or risperidone. In order to blood samples were obtained by cardiac puncture, allowed to generate dose-response curves raw CVs were converted to clot and then centrifuged at 12,000 rpm for 10 minto yield percentage maximum possible catalepsy (% MPC):% MPC= US 2009/0053329 A1 Feb. 26, 2009 20

((CV drug or drug combination—CV vehicle control)/(120 blockade in the pituitary. This is critical with respect to ris CV vehicle control))*100. The dose that elicits 50% of maxi peridone which has been shown to preferentially occupy D. mum catalepsy (CDs) and the corresponding 95% CI was receptors in the pituitary gland, as compared to the striatum, determined for each compound as previously mentioned. at doses up to 2.5 mg/kg in rats. If risperidone does indeed Each dose or dose combination was assessed in separate poorly cross the BBB then the profile of this drug is more groups of rats. consistent with a typical, rather than an atypical APD, as the 0200 Effects of pimavanserin on haloperidol- and risperi direct effects at D in the pituitary are not likely to be coun done-induced catalepsy in rats: FIG. 21A depicts dose teracted by 5-HT, receptor blockade inside the BBB. Con response curves as a function of haloperidol dose. As sistent with this idea are the observations in the present study expected, haloperidol (open circles) produced a dose-depen in which it was shown that risperidone elevates prolactin at dent increase in catalepsy time in rats. Pimavanserin failed to doses equal to or below those required to attenuate head potentiate haloperidol-induced catalepsy at any of the doses twitches produced by DOI. Furthermore, by combining pima tested. The combination of 1 (filled circles) or 3 mg/kg (open vanserin with risperidonea sufficient level of 5-HT, receptor squares) of pimavanserin with haloperidol did not signifi occupancy was reached inside the BBB to counteract risperi cantly alter haloperidol-induced catalepsy, CDso values of done-induced hyperprolactinemia. Taken together, these data 0.24 mg/kg (0.16-0.36: 95% CI) and 0.38 mg/kg (0.24-0.61; indicate that risperidone is not likely to achieve maximum 95% CI), respectively. However, the addition of 10 mg/kg occupancy of 5-HT, receptors inside the BBB, in the pimavanserin (filed squares) to haloperidol significantly absence of significant D receptor antagonism, in rats or in increased the observed CDs value from 0.27 mg/kg (0.19-0. humans. These finding have significant clinical relevance, as 39; 95% CI) to 0.53 mg/kg (0.31-0.91; 95% CI) indicating a hyperprolactinemia is correlated with numerous complica reduction of catalepsy. tions such as sexual dysfunction, which is a prominent cause 0201 FIG.21B depicts dose response curves as a function of noncompliance, particularly in men, with these medica of risperidone dose. As expected, risperidone (open circles) tions. produced a dose-dependent increase in catalepsy time in rats. 0203 Finally, this investigation demonstrated that while Each data point represents a minimum n of 12. Vehicle treat both haloperidol and risperidone produced dose-dependent ment elicited a maximum CV of 6.8+0.9 sec. Pimavanserin catalepsy, pimavanserin alone did not elicit detectable cata did not elicit catalepsy at doses up to 10 mg/kg achieving a lepsy at doses as high as 10 mg/kg, or 50-fold higher than the maximum CV of 10.5+2.4 sec. a value that was not signifi IDs in a DOI head twitch assay, consistent with its lack of cantly different from that obtained in vehicle treated controls. affinity for D receptors. It was demonstrated that although In contrast, both haloperidol and risperidone produced dose pimavanserin potentiated the efficacy of haloperidol and ris dependent and marked increases in CVs yielding CDso values peridone, pimavanserin clearly did not potentiate the cata of 0.27 mg/kg (0.19-0.39; 95% CI) and 1.1 mg/kg (0.79-1.62: lepsy produced by either drug. Instead, a small but significant 95% CI), respectively. Pimavanserin, at all doses tested, reduction of haloperidol-induced catalepsy at a dose of pima resulted in a dose-dependent and significant rightward dis vanserin was observed that would be expected for supramaxi placement of the risperidone dose response curve for cata mal 5-HT, receptor occupancy (i.e., 10 mg/kg). Pimavan lepsy. The calculated CDso values for risperidone in the pres serin demonstrates approximately 50-fold selectivity for ence of 1 (filled circles), 3 (open squares) or 10 mg/kg (filed 5-HT, over 5-HT. This result suggests that the attenuation squares) pimavanserin were 2.0 mg/kg (1.3-3.0; 95% CI), 4.4 of catalepsy by pimavanserin may be driven by its weaker mg/kg (2.6-7.5: 95% CI) and 5.1 mg/kg (3.2-8.3: 95% CI), 5-HT, receptor interactions. Based on the in vivo data, the respectively, indicating a reduction of catalepsy. selectivity of pimavanserin for 5-HT, over 5-HT, receptors would be approximately 50-fold, which is in agreement with 0202 Discussion: Antagonism of D receptors produces previously published in vitro data. Pimavanserin also pro robust prolactinemia both experimentally and clinically. duced a significant attenuation of risperidone-induced cata Similarly, risperidone, an atypical APD, has also been shown lepsy, however, at doses as low as 1 mg/kg. The apparent shift to elicit prolactinemia as severe as haloperidol in humans. In in potency shown by pimavanserin against risperidone-in the present investigation, it was demonstrated that while both haloperidol and risperidone produced robust increases in duced catalepsy is likely a function of the excess of 5-HT serum prolactin, pimavanserin alone did not elevate, and antagonist expected to be present at doses of risperidone that indeed slightly reduced, serum prolactin levels. Importantly, would presumably occupy >70% of striatal D receptors. pimavanserin did not potentiate, but rather attenuated the Therefore, in a system that is in far excess of maximal 5-HT, hyperprolactinemia produced by these APDs. Despite the receptor occupancy, as would be expected with these dose anatomical evidence supporting expression of 5-HT, recep combinations, weaker 5-HT, antagonist properties of pima tors in the pituitary gland, the preponderance of data Suggests Vanserin, and perhaps risperidone, are more likely to mani that the regulation of prolactin secretion mediated by 5-HT, fest. receptors occurs at the level of the hypothalamus. Pituitary D. receptors, which lie outside of the blood brain barrier (BBB), Example 6 exert tonic inhibition of prolactin secretion, while activation Prolactin Levels During Co-Administration of Pima of 5-HT, receptors in the hypothalamus inhibits DA release vanserin with Risperidone resulting in prolactin elevation. Thus, pure D antagonists elicit prolactinemia by direct actions in the pituitary, whereas, 0204 Prolactin levels were measured during a Phase II highly brain penetrating APDs, especially those which pos Schizophrenia co-therapy trial using pimavanserin in combi sess high 5-HT/D affinity ratios (i.e., olanzapine and nation with risperidone and compared to administration of clozapine), do not elicit marked hyperprolactinemia because risperidone alone. As depicted in the FIG. 22 graph, patients these drugs achieve sufficient 5-HT, receptor blockade in in the co-therapy arm with pimavanserin plus risperidone (2 the hypothalamus to counteract the effects of D receptor mg) had significantly lower prolactin levels after 42-days of US 2009/0053329 A1 Feb. 26, 2009 treatment as compared to patients in the risperidone (6 mg) plus placebo arm (p=0.00001). 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) 0205 Plasma Concentration-Time Profile Following Oral Elimination rate constant O.2393 (k10) (1/hr) Administration of 20 mg of Pimavanserin Once Daily Alpha (1/hr) O4314 0206. Initial parameters for the simulation were obtained Beta (1/hr) O.O349 by fitting mean plasma concentration-time data to a 1-com CL/F (L/hr) 14408.8 partment model (first order input, no lag time and first order V2/F (mL) 157245.7 CLD2/F (mL/hr) 9885.5 elimination). Mean multiple-dose plasma concentration-time Tmax (hr) 2.4 data following the 14" oral dose of 50 mg of pimavanserin Cmax (ng/mL) 25.8 were applied. Based on the model, the pharmacokinetic AUC (hring/mL) 277.6 parameters shown in Table 4 were estimated. 0211. The pharmacokinetic parameters provided in Table TABLE 4 6 agreed reasonably well with previous reported pharmaco Pharmacokinetic parameters obtained by fitting kinetic parameters for risperidone. However, the secondary pimavanserin mean plasma concentration-time parameters were poorly estimated by the model as indicated data (50 mg) to 1-compartment model. by the coefficient of variation of the parameters. Pharmacokinetic parameter Estimate 0212. The plasma concentration-time profile of risperi done following oral administration of 5 mg of risperidone Absorption rate constant (k01) (1/hr) O.91.97 once daily was simulated using the initial parameters pro Elimination rate constant (k10) (1/hr) O.O121 CL/F (L/hr) 6.4 vided in Table 7. The simulated profile for risperidone admin Tmax (hr) 4.77 istered alone are shown in FIG. 23. Cmax (ng/mL) 89.27 AUC (0-24)ss (hiring/mL) 1893.2 TABLE 7 Initial parameters used in simulation of plasma concentration-time 0207. The pharmacokinetic parameters provided in Table profile of risperidone following oral administration 4 agreed well with previous reported pharmacokinetic param of 5 mg of risperidone once daily. eters obtained following multiple oral doses of pimavanserin. One exception is the oral clearance for which the estimated Parameter Value parameter is somewhat lower compared to the previous V1/F (mL) 60222 reported value (25.2 L/hr). KO1 (1/hr) O4403 0208. The plasma concentration-time profile of pimavan CL/F (mL/hr) 14409 serin following oral administration of 20 mg of pimavanserin V2/F (mL) 157246 once daily was simulated using the initial parameters pro CLD2/F (mL/hr) 9886 vided in Table 5. The simulated profile for pimavanserin administered alone are shown in FIG. 23. 0213 Due to the shorter half-life of risperidone, 19.9 hr compared to 57.3 for pimavanserin, fluctuations between TABLE 5 peak and trough plasma concentrations are seen to be higher for risperidone. Steady state concentrations of pimavanserin Initial parameters used in simulation of plasma concentration-time are reached following approximately 200hr corresponding to profile of pimavanserin following oral administration 8 days. Cass and Class for pimavanserin are approxi of 20 mg of pimavanserin Once daily. mately 27.2 and 34.5 ng/1 mL, respectively. The steady state Parameter Value maximum concentrations are reached approximately 4 hours post dosing. V/F (mL) 2182727 KO1 (1/hr) O.91.97 0214. Simulation of the Time Course of Serotonin CL/F (mL/hr) 26411: 5-HT2A and Dopamine D2 Receptor Occupancy from Plasma Pharmacokinetics of Pimavanserin and Risperidone *Calculated using D/AUCo. 24. 0215. The receptor occupancy (d.96) was calculated using 0209 Plasma Concentration-Time Profile Following Oral equation 1, d=(C/C+Kd)*100, where C is the concentra Administration of 5 mg of Risperidone Once Daily tion of unbound drug around the receptor (nM) and Kd is the 0210. Initial parameters for the simulation were obtained dissociation constant (nM). by fitting mean plasma concentration-time data to a 2-com 0216 C is assumed to equal the unbound drug concen partment model (first order input, micro-constants, no lag tration in plasma implying that equilibrium between plasma time and first orderelimination). Mean plasma concentration and brain is fast and no active transport of the drug takes place time data obtained following administration of a single oral during distribution to the brain. C may then be calculated dose of 4 mg of risperidone were applied. Based on the model, using equation 2, Co. f*C.(t), wheref, is the free fraction of the pharmacokinetic parameters shown in Table 6 were esti drug in plasma and Cf(t) is the plasma concentration at time mated. t. US 2009/0053329 A1 Feb. 26, 2009 22

0217. 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 decreased in the combination. The receptor occupancy of D2 Unbound fraction in plasma and Kd remained Substantially unchanged. of pinavanserin and risperidone 0224. The D2 and 5HT receptor occupancy-time profiles Kd (nM for paliperidone (a metabolite of risperidone) following therapy with risperidone alone at 3 mg twice daily is shown in f, SHT2A D2 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 0218. 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 risper istered separately is shown in FIG. 24. Risperidone, which done 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 0219. Following the first oral dose of 20 mg of pimavan D2 remained Substantially unchanged. serin 71% 5HT2A receptor occupancy is achieved 5 hr post 0225. 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 shown in FIG. 28A. The D2 and 5HT receptor occupancy receptor occupancies for pimavanserin vary between 88 and time profiles following combined therapy with pimavanserin 91%. and risperidone is shown in FIG. 28B. The pimavanserin dose 0220. The calculated occupancy of 5HT2A and D2 recep was maintained at 20 mg daily and the risperidone dose was tors 2.4 hours after the first oral dose of 5 mg of risperidone is maintained at 3 mg twice daily. FIGS. 28A and 28B further 98% and 96%, respectively. The corresponding plasma con illustrate that receptor occupancy of 5HT was slightly centration of risperidone is 32.3 ng/mL. The steady state D2 enhanced with combined pimavanserin and risperidone receptor occupancy of risperidone ranges between 80% and therapy versus risperidone therapy alone when dosing at 3 mg 97%. Occupancy of the 5HT receptor in steady state is twice daily. The receptor occupancy of D2 remained substan between 86% and 98%. The corresponding minimum and tially unchanged. maximum steady state plasma concentrations of risperidone 0226. The D2 and 5HT receptor occupancy-time profiles are 4.9 ng/mL and 36.6 ng/mL. following therapy with 1 mg twice daily of risperidone alone 0221) The receptor occupancy-time profile of D2 and 5HT is shown in FIG. 29A. The D2 and 5HT receptor occupancy receptors following combined therapy with pimavanserinand time profiles following combined therapy with pimavanserin risperidone is shown in FIG. 25. The pimavanserin dose was and risperidone is shown in FIG.29B. The pimavanserin dose maintained at 20 mg once daily as in FIG. 24, whereas the was maintained at 20 mg daily and the risperidone dose was daily dose of risperidone has been reduced to 1 mg once daily. maintained at 1 mg twice daily. For FIGS. 29A and 29B, the The results indicate that D2 receptor occupancy significantly contribution from paliperidone to the receptor profiles was decreases as compared to the higher dose of risperidone not taken into account. FIGS. 29A and 29B illustrate that administered alone (see FIG. 24) while the 5HT receptor receptor occupancy of 5HT was significantly enhanced with occupancy is maintained at high level. These results Support combined pimavanserin and risperidone therapy versus ris that the combination can lead to a lower incidence of D2 peridone therapy alone at 1 mg twice daily dosing. The varia related side effects without affecting 5HT associated efficacy. tion in 5HT receptor occupancy decreased substantially in the 0222. The D2 receptor occupancy was calculated using combination, demonstrating the beneficial effect of combin equation 1. The 5HT receptor occupancy was calculated ing the long acting pimavanserin with the short acting risperi using equation 3: D-(CR1/(CR1+Kdsir (1+CR2/Kdsz))+ done. The receptor occupancy of D2 remained Substantially (Cr2/(Cr2+Kdsize (1+C/Kdsz)))*100, where C1, C2, unchanged. Comparison with FIG. 26B (illustrating a 3 mg Kds, Kdsize is the unbound concentration of pimavan twice daily dose of risperidone) illustrates a more significant serin, unbound concentration of risperidone, dissociation enhancement in 5HT receptor occupancy with a decreased constant of pimavanserin for 5HT2A receptor and dissocia D2 receptor occupancy. tion constant of risperidone for 5HT2A, respectively. 0227. The D2 and 5HT receptor occupancy-time profiles 0223 Several other doses of risperidone were also evalu for paliperidone following therapy with 1 mg twice daily ated. The D2 and 5HT receptor occupancy-time profiles fol risperidone alone is shown in FIG. 30A. The D2 and 5HT lowing therapy with 3 mg twice daily of risperidone alone is receptor occupancy-time profiles for paliperidone following shown in FIG. 26A. The D2 and 5HT receptor occupancy combined therapy with pimavanserin and risperidone is time profiles following combined therapy with pimavanserin shown in FIG.30B. The pimavanserin dose was maintained at and risperidone is shown in FIG. 26B. The pimavanserin dose 20 mg daily and the risperidone dose was maintained at 1 mg was maintained at 20 mg daily, and the risperidone dose was twice daily. For FIGS. 30A and 30B, the contribution from maintained at 3 mg twice daily. The contribution from pali risperdone to the receptor profiles was not taken into account. peridone to the receptor profiles was not taken into account. FIGS.30A and 30B illustrate that receptor occupancy of 5HT US 2009/0053329 A1 Feb. 26, 2009

was significantly enhanced with combined pimavanserin and 35-40. (canceled) risperidone therapy versus risperidone therapy alone at 1 mg 41. A method of increasing patient compliance during twice daily dosing. A decrease in 5HT receptor occupancy antipsychotic therapy, comprising co-administering a variation was also observed in the combination. The receptor 5-HT2A inverse agonist or antagonist with an antipsychotic occupancy of D2 remains Substantially unchanged. Compari agent, wherein the doses of co-administration are Such that son with FIG. 27B (illustrating a 3 mg twice daily dose of patient compliance is increased as compared to compliance risperidone) illustrates a more significant enhancement in 5HT receptor occupancy with a decreased D2 receptor occu when administering an efficacious dose of the antipsychotic pancy. agent alone. 0228. The D2 and 5HT receptor occupancy-time profiles 42. The method of claim 41, wherein the 5-HT2A inverse following therapy with 1 mg twice daily taking both risperi agonist or antagonist is the compound of formula (I): done and paliperidone into account is shown in FIG.31A. The D2 and 5HT receptor occupancy-time profiles following combined therapy with pimavanserin and risperidone is (I) shown in FIG.31B. The pimavanserin dose was maintained at CH3 20 mg daily and the risperidone dose was maintained at 1 mg twice daily. FIGS. 31A and 31B illustrate that receptor occu pancy of 5HT was significantly enhanced with combined pimavanserin and risperidone therapy versus risperidone therapy alone at 1 mg twice daily dosing. A decrease in 5HT receptor occupancy variation was also observed in the com H bination. The receptor occupancy of D2 remained Substan N N tially unchanged. Comparison with FIG. 28B (illustrating a 3 mg twice daily dose of risperidone) illustrates a more signifi r cant enhancement in 5HT receptor occupancy with a O decreased D2 receptor occupancy. 0229. Taken together, FIGS. 24-31B demonstrate that or a pharmaceutically acceptable salt thereof. combinations of pimavanserin and low doses of risperidone 43. The method of claim 41, wherein the antipsychotic can result in an enhancement of the receptor occupancy of the agent is risperidone. 5HT2A receptor compared with low dose risperidone therapy 44.-48. (canceled) alone and achieve a lower D2 receptor occupancy due to the 49. A method of reducing or preventing one or more side lower dose of risperidone. Thus, a combined therapy with effects associated with administration of an antipsychotic pimavanserin and risperidone can increase the efficacy of agent, comprising co-administering a 5-HT2A inverse ago anti-psychotic treatment without increasing side effects due nist or antagonist with the antipsychotic agent to a subject at to D2 receptor occupancy. Furthermore, the results demon strate that combining the long acting drug pimavanserin with risk of or suffering from said one or more side effects. the short acting drug risperidone results in significantly less 50. The method of claim 49, wherein the 5-HT2A inverse variability in 5-HT2A receptor occupancy, allowing the high agonist or antagonist is the compound of formula (I): levels of occupancy to be maintained between dosings. 0230. Although the invention has been described with ref erence to embodiments and examples, it should be under (I) stood that numerous and various modifications can be made CH3 without departing from the spirit of the invention. Accord ingly, the invention is limited only by the following claims. 1.-32. (canceled) 33. A method of inducing a rapid onset of an antidepressant F - effect, comprising co-administering a 5-HT2A inverse ago H nist or antagonist and an antipsychotic agent to a subject N N Suffering from depression Such that there is a rapid onset of antidepressant effect. r 34. The method of claim 33, wherein the 5-HT2A inverse O agonist or antagonist is the compound of formula (I): or a pharmaceutically acceptable salt thereof. 51. The method of claim 50, wherein the antipsychotic (I) agent is risperidone. CH 52.-70. (canceled) 71. The method of claim 49, wherein the one or more side effects are selected from the group consisting of stroke, trem ors, sedation, gastrointestinal problems, neurological prob F -l lems, increased risk of death, cerebrovascular events, move H ment disorder, dystonia, akathisia, parkinsoniam movement N N disorder, tardive dyskinesia, cognitive disorders, prolactine mia, catalepsy, psychosis, neuroleptic malignant syndrome, r heart problems, pulmonary problems, diabetes, liver failure, O Suicidality, sedation, orthostatic hypotension, choking, dizzi or a pharmaceutically acceptable salt thereof. ness, tachycardia, blood abnormalities, abnormal triglyceride US 2009/0053329 A1 Feb. 26, 2009 24 levels, increased cholesterol levels, dyslipidemia, hypergly 72. The method of claim 49, wherein the one or more side cemia, Syncope, seizures, dysphagia, priapism, thrombotic effects are selected from the group consisting of weight gain, thrombocytopenic purpura, disruption of body temperature increased serum glucose, hyperprolactinemia or a combina regulation, insomnia, agitation, anxiety, Somnolence, aggres tion thereof. 73. The method of claim 49, wherein the side effect is sive reaction, headache, constipation, nausea, dyspepsia, Weight gain. Vomiting, abdominal pain, saliva increase, toothache, rhinitis, 74. The method of claim 49, wherein the side effect is coughing, sinusitis, pharyngitis, dyspnea, back pain, chest increased serum glucose. pain, fever, rash, dry skin, seborrhea, increased upper respi 75. The method of claim 49, wherein the side effect is ratory infection, abnormal vision, arthralgia, hypoaesthesia, hyperprolactinemia. manic reaction, concentration impairment, dry mouth, pain, 76. The method of claim 49, wherein the 5-HT2A inverse fatigue, acne, pruritus, myalgia, skeletal pain, hypertension, agonist or antagonist is a compound selected from the group diarrhea, confusion, asthenia, urinary incontinence, sleepi consisting of: ness, increased duration of sleep, accommodation distur bance, palpitations, erectile dysfunction, ejaculatory dys function, orgastic dysfunction, lassitude, increased pigmentation, increased appetite, automatism, increased dream activity, diminished sexual desire, nervousness, depression, apathy, catatonic reaction, euphoria, increased libido, amnesia, emotional liability, nightmares, delirium, yawning, dysarthria, Vertigo, stupor, paraesthesia, aphasia, hypoesthesia, tongue paralysis, leg cramps, torticollis, hypo tonia, coma, migraine, hyperreflexia, choreoathetosis, anor 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, hypertrichosis, genital pruritus, urticaria, Ventricular tachy cardia, angina pectoris, premature atrial contractions, T wave inversion, ventricular extrasystoles, ST depression, AV block, myocarditis, abnormal accommodation, Xerophthalmia, 77. The method of claim 1, wherein the 5-HT2A inverse diplopia, eye pain, blepharitis, photopsia, photophobia, agonist orantagonist is selected from the group consisting of abnormal lacrimation, hyponatremia, creatine phosphoki Adatanserin, Altanserin, Benanserin, Blonanserin, nase increase, thirst, weight decrease, decreased serum iron, Butanserin, Cinanserin, Eplivanserin, Fananserin, Fli cachexia, dehydration, hypokalemia, hypoproteinemia, banserin, Glemanserin, Iferanserin, Ketanserin, Lidanserin, hyperphosphatemia, hypertrigylceridemia, hyperuricemia, Mianserin, Pelanserin, Pruvanserin, Ritanserin, Seganserin, hypoglycemia, polyuria, polydipsia, hemturia, dysuria, uri and Tropanserin. nary retention, cystitis, renal insufficiency, arthrosis, Synos 78. The method of claim 50, wherein the antipsychotic tosis, bursitis, arthritis, menorrhagia, dry vagina, nonpeurp agent is haloperidol. 79. The method of claim 49, wherein the antipsychotic eral lactation, amenorrhea, female breast pain, leukorrhea, agent is selected from the group consisting of a phenothiaz mastitis, dysmenorrhea, female perineal pain, intermenstrual ine, a phenylbutylpiperidine, a dibenzapine, a benzisoxidil, bleeding, vaginal hemorrhage, increased SGOT, increased and a salt of lithium. SGPT. cholestatic hepatitis, cholecystitis, choleithiasis, hepa 80. The method of claim 51, wherein the dose of risperi titis, hepatocellular damage, epistaxis, Superficial phlebitis, done is less than about 6 mg per day. thromboplebitis, thrombocytopenia, tinnitus, hyperacusis, 81. The method of claim 51, wherein the dose of the com decreased hearing, anemia, hypochromic anemia, nor pound of formula (I) is from about 20 mg per day, and the dose mocytic anemia, granulocytopenia, leukocytosis, lymphad of risperidone is about 2 mg per day. enopathy, leucopenia, Pelger-Huet anomaly, gynecomastia, 82. The method of claim 78, wherein the dose of haloperi male breast pain, antiduretic hormone disorder, bitter taste, dol is less than about 3 mg per day. micturition disturbances, oculogyric crisis, abnormal gait, involuntary muscle contraction, and increased injury. c c c c c