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 to induce a rapid onset of antipsychotic action and increase the number of 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.

1 .- 32 . (canceled) 
   
   
       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): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       35 .- 40 . (canceled) 
   
   
       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): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       43 . The method of  claim 41 , wherein the antipsychotic agent is risperidone. 
   
   
       44 .- 48 . (canceled) 
   
   
       49 . A method of reducing or preventing one or more side effects 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 said one or more side effects. 
   
   
       50 . The method of  claim 49 , wherein the 5-HT2A inverse agonist or antagonist is the compound of formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       51 . The method of  claim 50 , wherein the antipsychotic agent is risperidone. 
   
   
       52 .- 70 . (canceled) 
   
   
       71 . The method of  claim 49 , wherein the one or more side effects are 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, paraesthesia, 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. 
   
   
       72 . The method of  claim 49 , wherein the one or more side effects are selected from the group consisting of weight gain, increased serum glucose, hyperprolactinemia or a combination thereof. 
   
   
       73 . The method of  claim 49 , wherein the side effect is weight gain. 
   
   
       74 . The method of  claim 49 , wherein the side effect is increased serum glucose. 
   
   
       75 . The method of  claim 49 , wherein the side effect is hyperprolactinemia. 
   
   
       76 . The method of  claim 49 , wherein the 5-HT2A inverse agonist or antagonist is a compound selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       77 . 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. 
   
   
       78 . The method of  claim 50 , wherein the antipsychotic agent is haloperidol. 
   
   
       79 . The method of  claim 49 , wherein the antipsychotic agent is selected from the group consisting of a phenothiazine, a phenylbutylpiperidine, a dibenzapine, a benzisoxidil, and a salt of lithium. 
   
   
       80 . The method of  claim 51 , wherein the dose of risperidone is less than about 6 mg per day. 
   
   
       81 . The method of  claim 51 , wherein the dose of the compound of formula (I) is from about 20 mg per day, and the dose of risperidone is about 2 mg per day. 
   
   
       82 . The method of  claim 78 , wherein the dose of haloperidol is less than about 3 mg per day.