Combinations of 5-ht2a inverse agonists and antagonists with antipsychotics

Abstract

Combinations of 5-HT2A inverse agonists or antagonists such as pimavanserin with antipsychotics such as risperidone are shown induce a rapid onset of antipsychotic action and increase the responders when compared to therapy with the antipsychotic alone. These effects can be achieved at a low dose of the antipsychotic, thereby reducing the incidence of side effects. The combinations are also effective at decreases the incidence of weight gain and increased glucose or prolactin levels caused by the antipsychotic.

What is claimed is: 
     
         1 . A method of treating a condition amenable to treatment with an antipsychotic, comprising:
 administering a first amount of a 5-HT2A inverse agonist or antagonist; and   administering a second amount of an antipsychotic agent, wherein the first and second amounts are such that an efficacious effect is achieved faster than when the antipsychotic agent is administered alone at an efficacious dose.   
     
     
         2 . The method of  claim 1 , wherein the second amount is less than a maximal dose of the antipsychotic agent when it is administered alone. 
     
     
         3 . The method of  claim 1 , wherein the second amount is less than an efficacious dose of the antipsychotic agent when it is administered alone. 
     
     
         4 . The method of  claim 1 , wherein the first and second amounts are such that the severity or onset of one or more side effects due to the antipsychotic agent are reduced as compared to administration of an efficacious dose of the antipsychotic agent alone. 
     
     
         5 . The method of  claim 4 , wherein the side effect is weight gain. 
     
     
         6 . The method of  claim 4 , wherein the side effect is selected from the group consisting of an extrapyramidal side effect, a histamine side effect, an alpha adrenergic side effect, and an anticholinergic side effect. 
     
     
         7 . The method of  claim 4 , wherein the side effect is selected from the group consisting of stroke, tremors, sedation, gastrointestinal problems, neurological problems, increased risk of death, cerebrovascular events, movement disorder, dystonia, akathisia, parkinsoniam movement disorder, tardive dyskinesia, cognitive disorders, prolactinemia, catalepsy, psychosis, neuroleptic malignant syndrome, heart problems, pulmonary problems, diabetes, liver failure, suicidality, sedation, orthostatic hypotension, choking, dizziness, tachycardia, blood abnormalities, abnormal triglyceride levels, increased cholesterol levels, dyslipidemia, hyperglycemia, syncope, seizures, dysphagia, priapism, thrombotic thrombocytopenic purpura, disruption of body temperature regulation, insomnia, agitation, anxiety, somnolence, aggressive reaction, headache, constipation, nausea, dyspepsia, vomiting, abdominal pain, saliva increase, toothache, rhinitis, coughing, sinusitis, pharyngitis, dyspnea, back pain, chest pain, fever, rash, dry skin, seborrhea, increased upper respiratory infection, abnormal vision, arthralgia, hypoaesthesia, manic reaction, concentration impairment, dry mouth, pain, fatigue, acne, pruritus, myalgia, skeletal pain, hypertension, diarrhea, confusion, asthenia, urinary incontinence, sleepiness, increased duration of sleep, accommodation disturbance, palpitations, erectile dysfunction, ejaculatory dysfunction, 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, paresthesia, aphasia, hypoesthesia, tongue paralysis, leg cramps, torticollis, hypotonia, coma, migraine, hyperreflexia, choreoathetosis, anorexia, flatulence, stomatitis, melena, hemorrhoids, gastritis, fecal incontinence, erutation, gastroeophageal reflux, gastroenteritis, esophagitis, tongue discoloration, choleithiasis, tongue edema, diverticulitis, gingivitis, discolored feces, gastrointestinal hemorrhage, hematemesis, edema, rigors, malaise, pallor, enlarged abdomen, ascites, sarcoidosis, flushing, hyperventilation, bronchospasm, pneumonia, tridor, asthma, increased sputum, aspiration, photosensitivity, increased sweating, acne, decreased sweating, alopecia, hyperkeratosis, skin exfoliation, bullous eruption, skin ulceration, aggravated psoriasis, furunculosis, verruca, dermatitis lichenoid, hypertrichosis, genital pruritus, urticaria, ventricular tachycardia, angina pectoris, premature atrial contractions, T wave inversion, ventricular extrasystoles, ST depression, AV block, myocarditis, abnormal accommodation, xerophthalmia, diplopia, eye pain, blepharitis, photopsia, photophobia, abnormal lacrimation, hyponatremia, creatine phosphokinase increase, thirst, weight decrease, decreased serum iron, cachexia, dehydration, hypokalemia, hypoproteinemia, hyperphosphatemia, hypertrigylceridemia, hyperuricemia, hypoglycemia, polyuria, polydipsia, hemturia, dysuria, urinary retention, cystitis, renal insufficiency, arthrosis, synostosis, bursitis, arthritis, menorrhagia, dry vagina, nonpeurperal lactation, amenorrhea, female breast pain, leukorrhea, mastitis, dysmenorrhea, female perineal pain, intermenstrual bleeding, vaginal hemorrhage, increased SGOT, increased SGPT, cholestatic hepatitis, cholecystitis, choleithiasis, hepatitis, hepatocellular damage, epistaxis, superficial phlebitis, thromboplebitis, thrombocytopenia, tinnitus, hyperacusis, decreased hearing, anemia, hypochromic anemia, normocytic anemia, granulocytopenia, leukocytosis, lymphadenopathy, leucopenia, Pelger-Huet anomaly, gynecomastia, male breast pain, antiduretic hormone disorder, bitter taste, micturition disturbances, oculogyric crisis, abnormal gait, involuntary muscle contraction, and increased injury. 
     
     
         8 . The method of  claim 1 , wherein the condition is psychosis and the efficacious effect is an antipsychotic effect. 
     
     
         9 . The method of  claim 8 , wherein, the psychosis is associated with schizophrenia. 
     
     
         10 . The method of  claim 8 , wherein the psychosis is acute psychotic exacerbation. 
     
     
         11 . The method of  claim 1 , wherein the 5-HT2A inverse agonist of antagonist is the compound of formula (I): 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 11 , wherein the antipsychotic agent is risperidone. 
     
     
         13 . The method of  claim 1 , wherein the 5-HT2A inverse agonist or antagonist is a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The method of  claim 1 , wherein the 5-HT2A inverse agonist or antagonist is selected from the group consisting of Adatanserin, Altanserin, Benanserin, Blonanserin, Butanserin, Cinanserin, Eplivanserin, Fananserin, Flibanserin, Glemanserin, Iferanserin, Ketanserin, Lidanserin, Mianserin, Pelanserin, Pruvanserin, Ritanserin, Seganserin, and Tropanserin. 
     
     
         15 . The method of  claim 1 , wherein the antipsychotic agent is a typical antipsychotic. 
     
     
         16 . The method of  claim 1 , wherein the antipsychotic agent is an atypical antipsychotic. 
     
     
         17 . The method of  claim 1 , wherein the antipsychotic agent is a D2 antagonist. 
     
     
         18 . The method of  claim 1 , wherein the antipsychotic agent is risperidone. 
     
     
         19 . The method of  claim 1 , wherein the antipsychotic agent is haloperidol. 
     
     
         20 . The method of  claim 1 , wherein the antipsychotic agent is selected from the group consisting of a phenothiazine, a phenylbutylpiperidine, a dibenzapine, a benzisoxidil, and a salt of lithium. 
     
     
         21 . The method of  claim 20 , wherein the phenothiazine is selected from the group consisting of chlorpromazine (Thorazine®), mesoridazine (Serentil®), prochlorperazine (Compazine®), thioridazine (Mellaril), Fluphenazine (Prolixin®), Perphenazine (Trilafon®), and Trifluoperazine (Stelazine®). 
     
     
         22 . The method of  claim 20 , wherein the phenylbutylpiperidine is pimozide (Orap®). 
     
     
         23 . The method of  claim 20 , wherein the dibenzapine is selected from the group consisting of clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®), and quetiapine (Seroquel®). 
     
     
         24 . The method of  claim 20 , wherein the benzisoxidil is ziprasidone (Geodon®). 
     
     
         25 . The method of  claim 20 , wherein the salt of lithium is lithium carbonate. 
     
     
         26 . The method of  claim 1 , wherein the antipsychotic agent is selected from the group consisting of Aripiprazole (Abilify®), Etrafon®, Droperidol (Inapsine®), Thioridazine (Mellaril®), Thiothixene (Navane®), Promethazine (Phenergan®), Metoclopramide (Reglan®), Chlorproxthixene (Taractan®), Triavil®, Molindone (Moban®), Sertindole (Serlect®), Droperidol, Amisulpride (Solian®), Melperone, Paliperidone (Invega®), and Tetrabenazine. 
     
     
         27 . The method of  claim 1 , wherein the condition amenable to treatment is selected from the group: consisting of schizophrenia, bipolar disorder, agitation, psychosis, behavioral disturbances in Alzheimer's disease, depression with psychotic features or bipolar manifestations, obsessive compulsive disorder, post traumatic stress syndrome, anxiety, personality disorders (borderline and schizotypal), dementia, dementia with agitation, dementia in the elderly, Tourette's syndrome, restless leg syndrome, insomnia, social anxiety disorder, dysthymia, ADHD and autism. 
     
     
         28 . The method of  claim 1 , wherein the administration is to a human less than eighteen years of age. 
     
     
         29 . The method of  claim 1 , comprising identifying a patient in need of a rapid onset of antipsychotic action. 
     
     
         30 . A method of inducing a rapid onset of an antipsychotic effect, comprising co-administering a 5-HT2A inverse agonist or antagonist and an antipsychotic agent to a subject suffering from psychosis such that there is a rapid onset of antipsychotic effect. 
     
     
         31 . The method of  claim 30 , wherein the 5-HT2A inverse agonist or antagonist is the compound of formula (I): 
       
         
           
           
               
               
           
         
       
     
     
         32 . The method of  claim 30 , wherein the antipsychotic agent is risperidone. 
     
     
         33 . A method of inducing a rapid onset of an antidepressant effect, comprising co-administering a 5-HT2A inverse agonist or antagonist and an antipsychotic agent to a subject suffering from depression such that there is a rapid onset of antidepressant effect. 
     
     
         34 . The method of  claim 33 , wherein the 5-HT2A inverse agonist or antagonist is the compound of formula (I): 
       
         
           
           
               
               
           
         
       
     
     
         35 . A method of increasing the percentage of patients responding to antipsychotic therapy, comprising co-administering a 5-HT2A inverse agonist or antagonist and an antipsychotic agent to a subject suffering from psychosis such that a greater percentage of patients experience an efficacious effect than when the antipsychotic agent is administered alone at an efficacious dose. 
     
     
         36 . The method of  claim 35 , wherein the 5-HT2A inverse agonist or antagonist is the compound of formula (1): 
       
         
           
           
               
               
           
         
       
     
     
         37 . The method of  claim 35 , wherein the antipsychotic agent is risperidone. 
     
     
         38 . A method of reducing or preventing weight gain associated with administration of an antipsychotic agent, comprising co-administering a 5-HT2A inverse agonist or antagonist with the antipsychotic agent to a subject at risk or of suffering from weight gain associated with administration of an antipsychotic agent. 
     
     
         39 . The method of  claim 38 , wherein the 5-HT2A inverse agonist or antagonist is the compound of formula (I): 
       
         
           
           
               
               
           
         
       
     
     
         40 . The method of  claim 38 , wherein the antipsychotic agent is risperidone. 
     
     
         41 . A method of increasing patient compliance during antipsychotic therapy, comprising, co-administering a 5-HT2A inverse agonist or antagonist with an antipsychotic agent, wherein the doses of co-administration are such that patient compliance is increased as compared to compliance when administering an efficacious dose of the antipsychotic agent alone. 
     
     
         42 . The method of  claim 41 , wherein the 5-HT2A inverse agonist or antagonist is the compound of formula (I): 
       
         
           
           
               
               
           
         
       
     
     
         43 . The method of  claim 41 , wherein the antipsychotic agent is risperidone. 
     
     
         44 . A method of reducing or preventing hyperprolactinemia caused by administration of risperidone, comprising co-administering a 5-HT2A inverse agonist or antagonist with less than 6 mg per day of risperidone to a subject at risk of or suffering from hyperprolactinemia associated with administration of risperidone. 
     
     
         45 . The method of  claim 44 , wherein the 5-HT2A inverse agonist or antagonist is the compound of formula (1): 
       
         
           
           
               
               
           
         
       
     
     
         46 . A method of reducing or preventing increased serum glucose associated with administration of an antipsychotic-agent, comprising co-administering a 5-HT2A inverse agonist or antagonist with the antipsychotic agent to a subject at risk of or suffering from increased serum glucose associated with administration of an antipsychotic agent. 
     
     
         47 . The method of  claim 46 , wherein the 5-HT2A inverse agonist or antagonist is the compound of formula (I): 
       
         
           
           
               
               
           
         
       
     
     
         48 . The method of  claim 46 , wherein the antipsychotic agent is risperidone. 
     
     
         49 . A method of reducing or preventing increased serum glucose and reducing or preventing weight gain associated with administration of an antipsychotic agent, comprising co-administering a 5-HT2A inverse agonist or antagonist with the antipsychotic agent to a subject at risk of or suffering from increased serum glucose and weight gain associated with administration of an antipsychotic agent. 
     
     
         50 . The method of  claim 49 , wherein the 5-HT2A inverse agonist or antagonist is the compound of formula (I): 
       
         
           
           
               
               
           
         
       
     
     
         51 . The method of  claim 50 , wherein the antipsychotic agent is risperidone. 
     
     
         52 . A pharmaceutical composition, comprising:
 a first amount of a 5-HT2A inverse agonist or antagonist; and   a second amount of an antipsychotic agent, wherein the first and second amounts are such that when the composition is administered, an efficacious antipsychotic effect is achieved faster than when the antipsychotic agent is administered alone at an efficacious dose.   
     
     
         53 . The pharmaceutical composition of  claim 52 , wherein the second amount is less than a maximal dose of the antipsychotic agent when it is administered alone. 
     
     
         54 . The pharmaceutical composition of  claim 52 , wherein the second amount is less than an efficacious dose of the antipsychotic agent when it is administered alone. 
     
     
         55 . The pharmaceutical composition of  claim 52 , wherein the 5-HT2A inverse agonist or antagonist is the compound of formula (I): 
       
         
           
           
               
               
           
         
       
     
     
         56 . The pharmaceutical composition of  claim 55 , wherein the antipsychotic agent is risperidone. 
     
     
         57 . A package, comprising:
 a first amount of a 5-HT2A inverse agonist or antagonist; and   instructions for administering the first amount of the 5-HT2A inverse agonist or antagonist and a second amount of an antipsychotic agent, wherein the first and second amounts are such that an efficacious antipsychotic effect is achieved faster than when the antipsychotic agent is administered alone at an efficacious dose.   
     
     
         58 . The package of  claim 57 , wherein the second amount is less than a maximal dose of the antipsychotic agent when it is administered alone. 
     
     
         59 . The package of  claim 57 , wherein the second amount is less than an efficacious dose of the antipsychotic agent when if is administered alone. 
     
     
         60 . The package of  claim 57 , wherein the 5-HT2A inverse agonist or antagonist is the compound of formula (I): 
       
         
           
           
               
               
           
         
       
     
     
         61 . The package of  claim 57 , wherein the antipsychotic agent is risperidone. 
     
     
         62 . A method of treatment, comprising:
 determining that a first pharmaceutical agent modulates a pharmacological property of a second pharmaceutical agent;   determining that the first pharmaceutical agent has a longer half-life than a second pharmaceutical agent; and   co-administering the first and second pharmaceutical agent to a patient.   
     
     
         63 . The method of  claim 62 , wherein the pharmacological property is receptor occupancy. 
     
     
         64 . The method of  claim 62 , wherein the pharmacological property is the minimum efficacious dose of the second pharmaceutical agent. 
     
     
         65 . The method of  claim 62 , wherein the half-life of the first agent is at least about 1.5 times higher than the half-life of the second agent. 
     
     
         66 . The method of  claim 62 , wherein 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. 
     
     
         67 . The method of  claim 62 , wherein the co-administration results in the second agent being present at an efficacious level during substantially all of the tune between successive dosing of the second agent and wherein said second agent would not have been present at an efficacious level for substantially all of the period between successive dosing if first agent had been administered alone with the same dosing schedule and dosage. 
     
     
         68 . The method of  claim 62 , wherein said first pharmacological agent and said second pharmacological agent are administered at doses and time intervals which result in said 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. 
     
     
         69 . 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 therapeutic 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.   
     
     
         70 . The method of  claim 69 , further comprising determining whether said test therapeutic agent enhances a level of receptor occupancy, wherein said receptor is targeted by said therapeutic agent.