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Home , Alentemol, Azaperone, Batelapine, Butaclamol, Butaperazine, Clopenthixol

USOO5955459A United States Patent (19) 11 Patent Number: 5,955,459 Bradley et al. (45) Date of Patent: Sep. 21, 1999

54 FATTY ACID- 5,795,909 8/1998 Shashoua et al...... 514/449 COMPOSITIONS AND USES THEREOF 5,827,819 10/1998 Yatvin et al...... 514/2 75 Inventors: Matthews O. Bradley, Laytonsville, FOREIGN PATENT DOCUMENTS Md.; Victor E. Shashoua, Belmont, 0599 576 A1 1/1994 European Pat. Off.. Mass.; Charles S. Swindell, Merion; 693498 1/1996 European Pat. Off.. Nigel L. Webb, Bryn Mawr, both of Pa. 06 072868 3/1994 Japan. 6072868 3/1994 Japan. 73 Assignee: Neuromedica, Inc., Conshohocken, Pa. 81513347082146 6/19963/1996 Japan. 9030963 2/1997 Japan. 21 Appl. No.: 08/979,312 WO 98/17325 4/1998 WIPO. 22 Filed: Nov. 26, 1997 OTHER PUBLICATIONS (51) Int. Cl." ...... A61R 31/395 Schabitz, WR, et al., “The Effects of Prolonged Treatment 52 U.S. Cl...... 514/220, 514/234, 514/255; With in Temporary Experimental Focal 514/321 Ischemia", J NeurolSci, 1996, 138(1-2):21–25. (Abstract). 58 Field of Search ...... 514220, 234, D’Orlando KJ, et al., “Citicoline (CDP-): Mecha 514/255,321 nisms of Action and Effects in Ischemic Brain Injury', s Neurol Res, 1995, 17(4): 281–284. Review. 56) References Cited Nishio K, et al., “Novel -Soluble Derivatives of Docosahexaenoic Acid Increase Diacyl-Glycerol Produc U.S. PATENT DOCUMENTS tion Mediated by -Specific Phospholi 3,539,573 11/1970 Schmutz et al...... poss pase C", Proc Soc Exp Biol Med, 1993, 203(2): 200-208. 4,097,597 6/1978 Horrom et al. ... 514220 Marder, Stephen R., J. Clin. Psychiatry (suppl 3) 57:9-13 4,558,049 12/1985 Lazzari et al...... 514/234 (1996). 4,692,441 9/1987 Alexander et al...... 514/194 Copy of Office Action in related case U.S. Serial No. 4,939,174 7/1990 Shashoua ...... 514/549 08/978,541. 5,112,863 5/1992 Hashimoto et al. ... 514/534 5,214,062 5/1993 Mark et al...... 514,369 Primary Examiner James H. Reamer 5,223,263 6/1993 Hostetler et al...... 424/450 Attorney, Agent, or Firm Wolf, Greenfield & Sacks, P.C. 5,308,832 5/1994 Garleb et al...... 514/2 5,411,947 5/1995 Hostetler et al. . ... 514/43 57 ABSTRACT 5,516,8005,466,841 11/19955/1996 Horrobin et...... al...... 514/560554/79 The invention provides compositions that include conjuill 5.532,374 7/1996 Saii et all 544/368 gates of a fatty acid molecule, preferably cis 560419s 2/1997 also et al. .514.6 docosahexaenoic acid, and antipsychotic agents. The con 5604,216 2/1997 Horrobin ...... 514/182 jugates are usefull in treating psychotic conditions Such as 5,646,180 7/1997 Chaturvedi ...... 514/471 . 5,654,290 8/1997 Bayon et al...... 514/77 5,750,572 5/1998 Bruzzese ...... 514/560 32 Claims, 5 Drawing Sheets U.S. Patent Sep. 21, 1999 Sheet 1 of 5 5,955,459

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O 5 O 15 2O 25 3O 35 Dose(umol/kg) Avg. 5 5,955,459 1 2 FATTY ACID-ANTIPSYCHOTC Seizure threshold and, in particular, agranulocytosis. The COMPOSITIONS AND USES THEREOF incidence of agranulocytosis in patients taking clozapine is about 1-2%. Agranulocytosis is a Serious condition charac RELATED APPLICATION terized by a precipitous drop in the white blood cell count; the seriousness of the condition mandates that white blood This application claims priority under 35 U.S.C. S 120 cell counts be measured each week for patients taking from U.S. patent application Ser. Nos. 08/651,428, and clozapine. Another patient compliance issue is the relatively 08/651,312, both filed May 22, 1996 the entire disclosures Short half life of clozapine in Vivo, which necessitates of which are incorporated herein by reference. multiple doses each day to maintain therapeutic effective BACKGROUND OF THE INVENTION CSS. Fatty acids previously have been conjugated with to Psychotic conditions Such as Schizophrenia and related help the drugs as conjugates cross the blood brain barrier. disorders (e.g. Schizoaffective disorder), are complex and For example, DHA (docosahexaenoic acid) is a 22 carbon heterogeneous diseases of uncertain etiology that afflict naturally-occurring, unbranched fatty acid that previously approximately 1 to 2% of all populations worldwide. 15 has been shown to be unusually effective in crossing the Schizophrenia is characterized as having both “positive blood brain barrier. When DHA is conjugated to a , the Symptoms” (hallucinations, delusions, and conceptual entire drug-DHA conjugate is transported acroSS the blood disorganization) and “negative Symptoms” (apathy, Social brain barrier and into the brain. DHA is attached via the acid withdrawal, affect, and poverty of Speech). Abnormal activ group to hydrophilic drugs and renders these drugs more ity of the neurotransmitter is a hallmark of Schizo hydrophobic (lipophilic). DHA is an important constituent phrenia. activity is reduced in the mesocor of the brain and recently has been approved as an additive tical System (resulting in negative symptoms) and is to infant formula. It is present in the milk of lactating enhanced in the mesolimbic System (resulting in positive or women. The mechanism of action by which DHA helps psychotic Symptoms). Several other neurotransmitters are drugs conjugated to it cross the blood brain barrier is involved, including , glutamate, and GABA. 25 unknown. For many years, Schizophrenia was treated with classical Another example of the conjugation of fatty acids to a antipsychotic drugs, the neuroleptics, that block central drug is the attachment of , an antipsychotic, to dopamine receptors. The neuroleptics are effective for treat Stearic acid, palnitic acid, enanthic acid, undecylenic acid or ing the positive Symptoms of Schizophrenia, but have little 2,2-dimethyl-palmitic acid. Pipotiazine is a drug that acts or no effect on the negative Symptoms. The ability of these within the central nervous System. The purpose of conju drugs to antagonize dopamine receptors correlates with gating pipotiazine to the fatty acids was to create an oily antipsychotic efficacy. Neuroleptic drugs include phenothi Solution of the drug as a liquid implant for Slow release of azines including aliphatics (e.g., ), pip the drug when injected intramuscularly. The release of the eridines (e.g., ), and (e.g., drug appeared to depend on the particular fatty acid Selected, fluiphenazine); (e.g., ); thioxan 35 and the drug was tested for its activity in the central nervous thenes (e.g., flupenthixol); Oxoindoles (e.g., ); System. dibenzoxazepines (e.g., ) and diphenylpiperidines Lipidic molecules, including the fatty acids, also have (e.g., ). been conjugated with drugs to render the conjugates more Unfortunately, neuroleptics-resistant negative Symptoms lipophilic than the drug. In general, increased lipophilicity account for most of the Social and vocational disability 40 has been Suggested as a mechanism for enhancing intestinal caused by Schizophrenia. Further, neuroleptics cause uptake of drugs into the lymphatic System, thereby enhanc , including rigidity, tremor, ing the entry of the conjugate into the brain and also thereby bradykinesia (slow movement), and bradyphrenia (slow avoiding first-pass metabolism of the conjugate in the liver. thought), as well as tardive and . 45 The type of lipidic molecules employed have included The atypical are a different class of antip phospholipids, non-naturally occurring branched and Sychotic drugs which have a different receptor binding unbranched fatty acids, and naturally occurring branched profile and effectiveness against the Symptoms of Schizo and unbranched fatty acids ranging from as few as 4 carbon phrenia. Atypical antipsychotics bind central Serotonin2 atoms to more than 30 carbon atoms. In one instance, (5-HT2) receptors in addition to D2 dopamine receptors. enhanced receptor binding activity was observed (for an Unlike the neuroleptics, they improve negative as well as 50 adenosine receptor ), and it was postulated that the positive Symptoms. They cause minimal extrapyramidal pendant lipid molecule interacted with the phospholipid Symptoms and rarely cause tardive dyskinesias, , or membrane to act as a distal anchor for the receptor ligand in acute dystonic reactions. the membrane microenvironment of the receptor. This The first drug approved for the 55 increase in , however, was not observed when the treatment of Schizophrenia was clozapine. Clozapine binds Same lipid derivatives of adenosine receptor antagonists D2 weakly, but has a strong affinity for were used, and generalizations thus were not made possible the 5-HT2A receptor. Clozapine also antagonizes by those studies. adrenergic, cholinergic, and histaminergic receptorS. Cloza SUMMARY OF THE INVENTION pine is effective for the treatment of Schizophrenia, espe 60 cially for Subjects who do not respond to traditional neuro It has now been discovered that covalent conjugates of a leptic therapy. Clozapine has been found to be Superior to fatty acid with clozapine have the unexpected property of neuroleptics for improving psychotic Symptoms, and gen extended therapeutic effectiveness. This unexpected prop erally is better tolerated. erty of the conjugate permits administration of lower doses The Side effects of clozapine, however, present problems 65 of drug (as part of the covalent conjugate) to yield an for Safety and patient compliance. The Side effects include antipsychotic therapeutic effect, thereby reducing the Sedation, orthoStatic hypotension, hypersalivation, lowered chances of Serious Side effects Such as agranulocytosis. The 5,955,459 3 4 unexpected property of the conjugate also permits leSS idazine; Thioridazine Hydrochloride; Thiothixene; Thio frequent dosing to maintain an antipsychotic therapeutic thixene Hydrochloride; Tioperidone Hydrochloride; effect relative to unconjugated clozapine. Hydrochloride; Hydrochloride; According to one aspect of the invention, a composition ; ; Triflupromazine Hydrochlo of matter is provided. The composition of matter is a 5 covalent conjugate of an antipsychotic agent and a fatty acid ride; and Hydrochloride. having 12–26 carbons. Preferably the fatty acid in an In certain preferred embodiments, involving composi unbranched common naturally occurring fatty acid. More tions of matter, the conjugate of the fatty acid and the preferably, the fatty acid has between 14 and 22 carbons. antipsychotic agent is Selected from the foregoing agents, Unbranched common naturally occurring fatty acids except that , butyrophenones and thioxan include C12:0 (lauric acid), C14:0 (myristic acid), C16:0 thenes are excluded. (palmitic acid), C16:1 (paalmitoleic acid), C16:2, C18:0 (Stearic acid), C18:1 (oleic acid), C18:1-7 (vaccenic), The most preferred fatty acid is docosahexaenoic acid. C18:2-6 (linoleic acid), C18:3-3 (O-linolenic acid), C18:3-5 The most preferred covalent conjugate is: r CH vvvvvvvyR \

(eleostearic), C18:3-6 (B-linolenic acid), C18:4-3, C20:1 According to another aspect of the invention, a pharma (gondoic acid), C20:2-6, C20:3–6 (dihomo-y-linolenic acid), ceutical composition is provided. The pharmaceutical com C20:4-3, C20:4-6 (arachidonic acid), C20:5-3 position includes a pharmaceutically acceptable carrier and (eicosapentaenoic acid), C22:1 (docoSenoic acid), C22:4-6 a covalent conjugate of an antipsychotic agent and a fatty (docosatetraenoic acid), C22:5-6 (docosapentaenoic acid), acid having 12–26 carbons. The covalent conjugate is C22:5-3 (docosapentaenoic), C22:6-3 (docosahexaenoic 35 present in the pharmaceutical composition in an amount acid) and C24:1-9 (nervonic). Highly preferred unbranched, effective for treating a psychotic condition. The preferred naturally occurring fatty acids are those with between 14 and fatty acids, bonds, antipsychotic agents and covalent con 22 carbon atoms. The most preferred fatty acid is docosa jugates are as described above. hexaenoic acid. The pharmaceutical composition also may comprise an Antipsychotic agents include: Maleate; 40 antipsychotic agent other than the covalent conjugate. Suit Hydrobromide; Alpertine, ; Batelap able Such antipsychotic agents are Selected from the group ine Maleate; ; Benzindopyrine Hydrochloride; consisting of Acetophenazine Maleate; Alentemol Hydro Brofoxine; ; Bromperidol Decanoate; bromide; Alpertine, AZaperone, Maleate, Ben Hydrochloride; ; Butaperazine peridol; Benzindopyrine Hydrochloride; Brofoxine; Bromp Maleate; Carphenazine Maleate; Carvotroline Hydrochlo 45 eridol; Bromperidol Decanoate; Butaclamol Hydrochloride; ride; Chlorpromazine; Chlorpromazine Hydrochloride; Butaperazine, Butaperazine Maleate, Carphenazine Male ; Cinperene; Cintriamide; Clomacran Phos ate; Carvotroline Hydrochloride; Chlorpromazine; Chlor phate, ; , Clopipazan MeSylate; Hydrochloride; Chlorprothixene; Cinperene; Cloroperone Hydrochloride; Clothiapine; Clothixamide Cintriamide; Clomacran Phosphate; Clopenthixol; Clopi Maleate; Clozapine; Cyclophenazine Hydrochloride; Dro 50 mozide; Clopipazan Mesylate; Cloroperone Hydrochloride; peridol; Etazolate Hydrochloride; Fenimide; ; Clothiapine; Clothixamide Maleate; Clozapine; Cyclo , Decanoate, Fluphenazine Enan phenazine Hydrochloride; ; Etazolate Hydrochlo thate; Fluphenazine Hydrochloride; Fluspiperone; Fluspir ride; Fenimide; Flucindole; Flumezapine; Fluphenazine ilene; Flutroline; Hydrochloride; Halopemide; Decanoate, Fluphenazine Enanthate, Fluphenazine Hydro Haloperidol; ; ; Imidoline 55 chloride; Fluspiperone; ; Flutroline; Gevotroline Hydrochloride; ; Succinate; Hydrochloride; Halopemide; Haloperidol; Haloperidol ; Mesoridazine Besylate; ; Milenper Decanoate, Iloperidone, Imidoline Hydrochloride; Lenper one; Milipertine; Molindone Hydrochloride; one, Mazapertine Succinate; MeSoridazine; MeSoridazine Hydrochloride; Neflumozide Hydrochloride; ; Besylate; Metiapine; Milenperone; Milipertine; Molindone ; Oxiperomide; ; Pentiapine Maleate; 60 Hydrochloride; Naranol Hydrochloride; Neflumozide ; Pimozide; Hydrochloride; Pipam Hydrochloride, Ocaperidone; Olanzapine, OXiperomide; perone, , Pipotiazine Palmnitate, Penfluridol; Pentiapine Maleate; Perphenazine; Pimozide; Hydrochloride; Edisylate; Prochlorpera Pinoxepin Hydrochloride; ; Piperacetazine; Zine Maleate; Promazine Hydrochloride; ; Pipotiazine Palmitate; Piquindone Hydrochloride; Prochlo ; Quetiapine Remoxipride Hydrochloride; Ris 65 rperazine Edisylate; Prochlorperazine Maleate; Promazine peridone; Risperadone Hydrochloride; Seperidol Hydrochloride; Quetiapine; Remoxipride; Remoxipride Hydrochloride; ; ; ; Thior Hydrochloride; ; Rimcazole Hydrochloride; 5,955,459 S 6 Seperidol Hydrochloride; Sertindole; Setoperone; Spiper FIG. 3 is a graph which shows a comparison of the one; Thioridazine; Thioridazine Hydrochloride; Thiothix activity over time of clozapine and DHA-clozapine against ene; Thiothixene Hydrochloride; Tioperidone Hydrochlo locomotor behavioral arousal induced by ride; Tiospirone Hydrochloride; Trifluoperazine when administered at 3 mg/kg. Hydrochloride; Trifluperidol; Triflu promazine; Triflupro FIG. 4 is a graph which shows a comparison of the mazine Hydrochloride; and Ziprasidone Hydrochloride. activity over time of clozapine and DHA-clozapine against According to another aspect of the invention, a kit is locomotor behavioral arousal induced by apomorphine provided. The kit comprises a package which houses a when administered at 10 mg/kg. container containing the covalent conjugate as described FIG. 5 is a graph which shows the molar-dose response of above. The package also houses instructions for administer clozapine and DHA-clozapine at the 360-420 min time ing the covalent conjugate to a Subject having a psychotic point for calculation of ED50. condition. DETAILED DESCRIPTION OF THE According to another aspect of the invention, a Second kit INVENTION is provided. The kit comprises a package which houses a first 15 container containing the covalent conjugate described above The invention involves the discovery that the extended and it further houses a Second container containing an therapeutic effectiveness can be achieved if conjugates of antipsychotic agent other than the covalent conjugate. antipsychotic agents and fatty acids are administered rather In the kits of the invention, the preferred fatty acids, than unconjugated antipsychotic agents. bonds, antipsychotic agents and conjugates are as described Clozapine is one of the class of "atypical antipsychotics, above. having the following Structure: According to another aspect of the invention, a method is provided for treating a psychotic condition. The method CH involves administering to a Subject in need of Such treatment r 3 a covalent conjugate of an antipsychotic agent and a fatty 25 acid having 12–26 carbons, in an amount effective to treat the psychotic condition. The preferred fatty acids, bonds, HN \ antipsychotic agents and conjugates are as described above. Likewise, cocktails as described above may be administered. According to another aspect of the invention, a method is provided for achieving in a Subject a therapeutic effect longer than the effect achieved if an equimolar amount of antipsychotic agents were administered. The method Cl involves administering to a Subject in need of Such treatment 35 a covalent conjugate of the antipsychotic agent and a fatty cis-docosahexaenoic acid (DHA) is a naturally occurring acid in an amount effective to achieve Said therapeutic effect. fatty acid. It is an unbranched chain fatty acid with Six The preferred fatty acids, bonds, antipsychotic agents and double bonds, all cis. Its structure is as follows: covalent conjugates are as described above. According to Still another aspect of the invention, a 40 OH method is provided for decreasing the number of daily doses required to achieve in a Subject a therapeutic effect equiva lent to that achieved if an equimolar amount of antipsychotic agent were administered to the Subject. The method involves administering to a Subject in need of Such treatment a 45 DHA can be isolated, for example, from fish oil or can be covalent conjugate of antipsychotic agents and a fatty acid chemically Synthesized. These methods, however, can gen in an amount effective to achieve Said therapeutic effect. erate trans isomers, which are difficult and expensive to Preferably, the covalent conjugate is administered not more Separate and which may present Safety problems in humans. than one time per day. The preferred fatty acids, bonds, The preferred method of production is biological Synthesis antipsychotic agents and covalent conjugates are as 50 to produce the all cis isomer. The preferred source of DHA described above. is from Martek Biosciences Corporation of Columbia, Maryland. Martek has a patented System for manufacturing These and other aspects of the invention are described DHA using microalgae which Synthesize only a single below. isomer of DHA, the all cis isomer. Martek’s patents include 55 U.S. Pat. Nos. 5,374,657, 5,492,938, 5,407,957 and 5,397, BRIEF DESCRIPTION OF THE DRAWINGS 591. FIG. 1 is a graph which shows the dose response over time DHA also is present in the milk of lactating women, and of clozapine against locomotor behavioral arousal induced Martek’s licensee has obtained approval in Europe of DHA by apomorphine. Clozapine 1, 3, 10 refer to doses of as a nutritional Supplement for infant formula. 60 It is known that DHA can be unstable in the presence of clozapine at 1, 3 and 10 mg/kg, respectively, administered oxygen. To Stabilize DHA and its conjugates it is important i.p. to add anti-oxidants to the material after it is Synthesized. FIG. 2 is a graph which shows the dose response over time One method of Stabilization is to make-up the newly Syn of DHA-clozapine against locomotor behavioral arousal thesized material in the following solution: 100 g neat induced by apomorphine. DHA-clozapine 1, 3, 10 refer to 65 DHA-clozapine plus 100 g of vehicle (100 ml propylene doses of DHA-clozapine at 1, 3 and 10 mg/kg, respectively, glycol, 70 mg alpha-tocopherol, 5 mg dialaurylthiodipropi administered i.p. onic acid, 50 mg ascorbic acid) prepared and held under 5,955,459 7 8 argon in amber, Sealed Vials and Stored at four degrees macologically and pharmaceutically acceptable Salts centigrade. The following anti-oxidants may also be include, but are not limited to, those prepared from the employed: ascorbic acid, ascorbyl palmitate, dilauryl following acids: hydrochloric, hydrobromic, Sulphuric, ascorbate, hydroquinone, butylated hydroxyanisole, Sodium metabisulfite, t-3 caroteine and C-tocopherol. A heavy metal nitric, phosphoric, maleic, acetic, Salicylic, p- chelator Such as ethylenediamine tetra-acetic acid (EDTA) Sulfonic, tartaric, citric, methane Sulfonic, formic, malonic, may also be used. Succinic, naphthalene-2-Sulfonic, and benzene Sulfonic. In one aspect of the invention, cocktails of the clozapine Also, pharmaceutically acceptable Salts can be prepared as fatty acid conjugate and another antipsychotic agent can be alkaline metal or alkaline earth Salts, Such as Sodium, prepared for administration to Subjects having a need for potassium or calcium Salts. such treatment. One of ordinary skill in the art is familiar Suitable buffering agents include: acetic acid and a Salt with a variety of antipsychotic agents which are used in the (1-2% W/V); citric acid and a salt (1–3% W/V); and medical arts to treat psychoseS Such as Schizophrenia. Antip phosphoric acid and a salt (0.8–2% W/V). Sychotic agents include Acetophenazine Maleate; Alentemol Suitable preservatives include benzalkonium chloride Hydrobromide, Alpertine, AZaperone; Batelapine Maleate; 15 (0.003–0.03% W/V); chlorobutanol (0.3–0.9% W/V); para Benperidol; BenZindopyrine Hydrochloride; Brofoxine; bens (0.01-0.25% W/V) and thimerosal (0.004–0.02% Bromperidol; Bromperidol Decanoate; Butaclamol Hydro W/V). chloride; Butaperazine; Butaperazine Maleate; Carphena The active compounds of the present invention may be a zine Maleate; Carvotroline Hydrochloride; Chlorpromazine; pharmaceutical composition having a therapeutically effec Chlorpromazine Hydrochloride; Chlorprothixene; Cin tive amount of a conjugate of the invention optionally perene, Cintriamide, Clomacran Phosphate, Clopenthixol; included in a pharmaceutically-acceptable carrier. The term Clopimozide; Clopipazan Mesylate; Cloroperone Hydro “pharmaceutically-acceptable carrier as used herein means chloride; Clothiapine; Clothixamide Maleate; Clozapine; one or more compatible Solid or liquid filler, dilutants or Cyclophenazine Hydrochloride; Droperidol; Etazolate 25 encapsulating Substances which are Suitable for administra Hydrochloride; Fenimide; Flucindole; Flumezapine; tion to a human or other animal. The term “carrier' denotes Fluphenazine Decanoate, Flu phena Zine Enant hate; an organic or inorganic ingredient, natural or Synthetic, with Fluphenazine Hydrochloride; Fluspiperone; Fluspirilene; which the active ingredient is combined to facilitate the Flutroline; Gevotroline Hydrochloride; Halopemide; Halo application. The components of the pharmaceutical compo peridol; Haloperidol Decanoate, Iloperidone, Imidoline Sitions are capable of being commingled with the molecules Hydrochloride; Lenperone; MaZapertine Succinate; of the present invention, and with each other, in a manner Mesoridazine; Mesoridazine Besylate; Metiapine; Milenper such that there is no interaction which would substantially one; Milipertine; Molindone Hydrochloride; Naranol impair the desired pharmaceutical efficacy. Hydrochloride; Neflumozide Hydrochloride; Ocaperidone; 35 Compositions Suitable for parenteral administration con Olanzapine; Oxiperomide; Penfluridol; Pentiapine Maleate; Veniently comprise a sterile preparation of the conjugates of Perphenazine; Pimozide; Pinoxepin Hydrochloride; Pipam the invention. This preparation may be formulated according perone, Piperacetazine, Pipotiazine Palmitate; Piquindone to known methods. Hydrochloride; Prochlorperazine Edisylate; Prochlorpera The Sterile preparation thus may be a sterile Solution or Zine Maleate; Promazine Hydrochloride; Quetiapine; 40 Suspension in a non-toxic parenterally-acceptable diluent or Remoxipride; Remoxipride Hydrochloride; Risperidone; Solvent. In addition, Sterile, fixed oils are conventionally Rimcazole Hydrochloride; Seperidol Hydrochloride; Sertin employed as a Solvent or Suspending medium. For this dole; Setoperone, Spiperone; Thioridazine; Thioridazine purpose any bland fixed oil may be employed including Hydrochloride; Thiothixene; Thiothixene Hydrochloride; 45 Synthetic mono or di-glycerides. In addition, fatty acids Such Tioperidone Hydrochloride; Tiospirone Hydrochloride; Tri as oleic acid find use in the preparation of injectables. fluoperazine Hydrochloride; Trifluperidol; Triflu promazine; Carrier formulations Suitable for oral, Subcutaneous, Triflupromazine Hydrochloride; and Ziprasidone Hydro intravenous, intramuscular, etc. can be found in Remington's chloride. Pharmaceutical Sciences, Mack Publishing Company, The compounds of the invention, when used in alone or 50 Easton, Pa. in cocktails, are administered in therapeutically effective The invention is used in connection with treating Subjects amounts. A therapeutically effective amount will be deter having, Suspected of having, developing or Suspected of mined by the parameters discussed below; but, in any event, developing a psychotic condition Such as Schizophrenia, or is that amount which establishes a level of the drug(s) 55 animals having or animals exhibiting Symptoms character effective for treating a psychotic disorder, including Schizo istic of Schizophrenia. phrenia. The conjugates of the invention, when used in alone or in When administered, the formulations of the invention are cocktails, are administered in effective amounts. An effec applied in pharmaceutically acceptable compositions. Such tive amount means that amount alone or with multiple doses, preparations may routinely contain Salts, buffering agents, 60 necessary to delay the onset of, inhibit completely or lessen preservatives, compatible carriers, and optionally other the progression of or halt altogether the onset or progression therapeutic ingredients. When used in medicine the Salts of the psychotic condition Such as Schizophrenia. In general, should be pharmaceutically acceptable, but non an effective amount will be that amount necessary to inhibit pharmaceutically acceptable Salts may conveniently be used 65 either negative or positive Symptoms of the psychotic to prepare pharmaceutically acceptable Salts thereof and are condition, and preferably both negative and positive Symp not excluded from the Scope of the invention. Such phar toms of the psychotic condition Such as Schizophrenia. The 5,955,459 9 10 inhibition of the negative and/or positive Symptoms of Step of bringing the conjugates of the invention into asso Schizophrenia can be monitored by Standard psychiatric ciation with a carrier which constitutes one or more acces evaluation of the Subject over time. In addition, other Sory ingredients. In general, the compositions are prepared physiological methods for monitoring the changes in brain by uniformly and intimately bringing the compounds into function which accompany Symptoms of Schizophrenia also asSociation with a liquid carrier, a finely divided Solid can be employed to monitor the inhibition of the Symptoms. carrier, or both, and then, if necessary, Shaping the product. For example, the State of advancement of Schizophrenia can Compositions Suitable for oral administration may be be assessed using magnetic resonance imaging (MRI) (see, presented as discrete units Such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the e.g., DeLisi et al., (Psychiatry Res. 74(3):129-140, 1997) or active compound. Other compositions include Suspensions positron emission tomography (PET) (See, e.g., Sabri et al., in aqueous liquors or non-aqueous liquids Such as a Syrup, Lancet 349:1735–1739, 1997; Andreasen et al., Lancet an elixir, or an emulsion. 349:1730–1734, 1997). When administered to a subject, 15 Other delivery Systems can include time-release, delayed effective amounts will depend, of course, on the particular release or Sustained release delivery Systems. Such Systems condition being treated; the Severity of the condition; indi can avoid repeated administrations of the active compounds vidual patient parameters including age, physical condition, of the invention, increasing convenience to the Subject and Size and weight; concurrent treatment, frequency of treat the physician. Many types of release delivery Systems are ment; and the mode of administration. These factors are well available and known to those of ordinary skill in the art. known to those of ordinary skill in the art and can be They include polymer based Systems. Such as polylactic and addressed with no more than routine experimentation. It is polyglycolic acid, polyanhydrides and polycaprolactone; preferred generally that a maximum dose be used, that is, the nonpolymer Systems that are lipids including Sterols Such as cholesterol, cholesterol esters and fatty acids or neutral fats highest Safe dose according to Sound medical judgment. 25 Such as mono-, di and triglycerides, hydrogel release Sys Dosage may be adjusted appropriately to achieve desired tems, Silastic Systems, peptide based Systems, wax coatings, drug levels, locally or Systemically. Generally, daily oral compressed tablets using conventional binders and doses of active compounds will be from about 0.01 mg/kg excipients, partially fused implants and the like. In addition, per day to 1000 mg/kg per day. It is expected that IV doses a pump-based hardware delivery System can be used, Some in the same range will be effective. In the event that the of which are adapted for implantation. response in a Subject is insufficient at Such doses, even A long-term Sustained release implant also may be used. higher doses (or effective higher doses by a different, more "Long-term release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of localized delivery route) may be employed to the extent that 35 patient tolerance permits. Continuous IV dosing over, for the active ingredient for at least 30 days, and preferably 60 example 24 hours or multiple doses per day also are con days. Long-term Sustained release implants are well known templated to achieve appropriate Systemic levels of com to those of ordinary skill in the art and include some of the pounds. release Systems described above. The preferred dose is believed to be at least /2, more 40 preferably 4 and even more preferably /6 or less than the EXAMPLE dose required to achieve the same therapeutic effect when an A) Synthesis of DHA-clozapine: equimolar amount of antipsychotic agent is administered but OH nonconjugated to a fatty acid. Clozapine typically is admin 45 istered in doses of 50-200 mg, 2-3 times per day. A variety of administration routes are available. The particular mode Selected will depend of course, upon the particular drug Selected, the Severity of the disease State 50 being treated and the dosage required for therapeutic effi cacy. The methods of this invention, generally speaking, C may be practiced using any mode of administration that is 55 medically acceptable, meaning any mode that produces DHA-chloride effective levels of the active compounds without causing clinically unacceptable adverse effects. Such modes of administration include oral, rectal, Sublingual, topical, nasal, Preparation of DHA-chloride: To a solution of DHA (2.0 g, 6.08 mmol) in CHCl (8 ml) transdermal or parenteral routes. The term "parenteral' 60 was added thionylchloride (2.22 ml, 30.4 mmol), at 0° C. includes Subcutaneous, intravenous, intramuscular, or infu under an Argon atmosphere and the reaction mixture was Sion. Oral routes are preferred, although administration by stirred at room temperature for 14 h. Excess thionylchloride injection may be practical. was removed by co-evaporation with dry benzene (6 ml) The compositions may conveniently be presented in unit 65 under reduced preSSure. The resulting acid chloride was dosage form and may be prepared by any of the methods dried in high vacuum and Subsequently used as Such for the well known in the art of pharmacy. All methods include the following reaction without purification. 5,955,459 11 12

CO\

DHA-chloride CLOZAPINE

CH Nur N1 vvvvvvvyR N CLOZAPINE-DHA

35 Preparation of Clozapine-DHA analog: Clozapine and DHA-clozapine were made-up to a 50% To a solution of clozapine (950 mg, 2.90 mmol) in dry W/w Solution in propylene glycol. This Solution was injected toluene (30 ml) was added dry pyridine (235ul, 2.90 mmol) directly into the peritoneum at the appropriate dose. followed by DHA-chloride (1.25 ml, 3.98 mmol) under an Physiological Measurements: Argon atmosphere at room temperature. The reaction mix 40 A Standard animal model of Schizophrenia Symptoms ture was refluxed for 3 h, cooled to room temperature, and (apomorphine increased hyper-locomotion) was used to stirred with 10% aq. NaCO solution (5 ml) for about 20 assess the activity of the DHA-clozapine conjugate. To Start min. The reaction mixture was washed with water (3x20 the experiment, 1.0 mg/kg of R(-)apomorphine was injected ml), the combined aqueous phase was extracted once with into the peritoneum of each rat, which caused the locomotor ether (20 ml), the organic phase was dried (Na2SO) and 45 activity of the rats to increase. The DHA-clozapine conju concentrated under reduced pressure. The residue was puri gate was then administered i.p., and the drug's effect on fied by chromatography on florisil with 98:2 CHCl apomorphine increased hyper-locomotion was measured methanol as eluent to yield the clozapine-DHA analog as an electronically in a computerized activity monitoring System. orange red viscous liquid (1.65 g, 89%). Results: NMR analysis of the product was as follows: 50 DHA-clozapine and clozapine were both active against "H NMR (300 MMZ, CDC1): 80.97 (t, J=7.6 Hz, 3 H), locomotor behavioral arousal induced by 1 mg/kg, i.p., of 2.07 (apparent quintet, J=7.4 Hz, 2 H), 2.15-2.29 (m, 8 R(-) apomorphine, within an hour after injection of the H), 2.29 (s, 3 H), 2.73–2.68 (m, 10 H), 3.48–3.90 (m, tested central depressants at doses of 10 mg/kg, i.p. (FIGS. 4H), 5.25-5.44 (m, 12 H), 6.96 (dd, J=8.4, 2.4 Hz, 1 1 & 2). H), 7.12 (d, J=8.4 Hz, 1 H), 7.36–7.50 (m, 3 H), 55 DHA-clozapine was much longer acting than clozapine, 7.25-7.55 (m, 1 H). in that the effect of doses of DHA-clozapine of 3 mg/kg, i.p., °C NMR (75 MHz, CDC1): 81422, 20.50 (), 22.82, persisted for 24 hours after administration. In contrast, the 25.48, 25.49 (2C), 25.578 (4C).33.44, 45.91, 54.66, effect of clozapine persisted weakly for not more than 2 or 123.19, 126.10, 126.65, 126.97, 127.63, 127.81, 127.83 4 hours at that dose. At 10 mg/kg, DHA-clozapine produced (2C), 128.07, 128.09, 128.15 (2C), 128.21 (2C), 128.51 60 profound inhibition of behavioral arousal that persisted for (2C), 129.07 (2C), 131.97, 132.01, 133.37, 133.94, longer than 25 hours, whereas behavior had returned to 144.72, 146.13, 160.29 and 172.98. control levels within 3-5 hours after administration of B) Methods of Use: clozapine. Thus, DHA-clozapine was at least Six-times Experimental Procedures longer-acting, and probably even more longer-acting if Animals: rats. 65 equimolar doses were compared. (FIGS. 2 & 3, in which Rats/group: nine. asterisks indicate p-0.05 for planned post-hoc comparisons Route of administration: i.p. by Scheffé's test after a two-way ANOVA for effect of drug 5,955,459 13 14 and testing time: F180 dif=80.3 at 3 mg/kg, and F1.80 df 4. The composition of matter of claim 2, wherein the fatty 146 at 10 mg/kg, both p<0.0001 for a difference between acid is docosahexaenoic acid. drugs). 5. A pharmaceutical composition comprising On a molar-dose basis (MW of clozapine=327; DHA a covalent conjugate of an antipsychotic agent and a fatty clozapine=637), with testing at hours 3–4 after dosing, acid having 12–26 carbons in an amount effective for DHA-CLZ produced 50% inhibition of locomotor arousal treating a psychotic condition, and induced by R(-)-apomorphine at about 3.5 umol/kg, i.p., a pharmaceutically acceptable carrier except that the whereas clozapine itself required a dose of about 22.5 antipsychotic agent is not a , butyrophe umol/kg to produce the same effect (FIG. 4). Thus, the none or , and wherein the antipsychotic DHA-derivative was approximately 6.4-times more potent. agent is Selected from the group consisting of Alente In conclusion, DHA-clozapine appears to be a potent, mol Hydrobromide; Alpertine; Batelapine Maleate; long-acting central depressant with powerful and prolonged Benzindopyrine Hydrochloride; Brofoxine; Bromperi antiapomorphine activity in the rat after Systemic injection, dol; Bromperidol Decanoate; Butaclamol Hydrochlo with the ED50 of about 3.5 timol/kg, i.p., and duration of ride; Butaperazine, Butaperazine Maleate; Carphena action of more than 24 hours after doses on the order of 15 zine Maleate; Carvotroline Hydrochloride; Cinperene; 10-15 umol/kg. Cintriamide; Clomacran Phosphate; Clopenthixol; Clo Such an increase in half-life has a number of medical pimozide, Clopipazan MeSylate; Cloroperone Hydro implications Such as better control of patients' psychotic chloride; Clothiapine; Clothixamide Maleate; Clozap Symptoms Since the longer half-life should allow "once a ine; Cyclophenazine Hydrochloride; Eta Zolate day dosing and at lower doses. Lower total doses should Hvdrochloride; Fenimide; Flucindole; Flumezapine; result in a decrease of the peripherally and perhaps centrally Fluspirilene; Flutroline; Gevotroline Hydrochloride; mediated Side-effects of clozapine. Halopemide; Iloperidone; Imidoline Hydrochloride; Other aspects of the invention will be clear to the skilled Lenperone, Mazapertine Succinate; Metiapine, Milen artisan and need not be repeated here. All patents, published perone; Milipertine; Molindone Hydrochloride; Nara patent applications and literature cited herein are incorpo 25 nol Hydrochloride; Neflumozide Hydrochloride; Oca rated by reference in their entirety. peridone; Olanzapine; Oxiperomide; Penfluridol; While the invention has been described with respect to Pentiapine Maleate; Pimozide; Pinoxepin Hydrochlo certain embodiments, it should be appreciated that many ride; Pipamperone; Piperacetazine; Pipotiazine Palmi modifications and changes may be made by those of ordi tate; Piquindone Hydrochloride; Quetiapine; Remox nary skill in the art without departing from the Spirit of the ipride; Quetiapine Remoxipride Hydrochloride; invention. It is intended that Such modification, changes and Risperidone; Risperadone Rimcazole Hydrochloride; equivalents fall within the Scope of the following claims. Seperidol Hydrochloride; Sertindole; Setoperone; Tio We claim: peridone Hydrochloride; TioSpirone Hydrochloride; 1. A composition of matter comprising and Ziprasidone Hydrochloride. a covalent conjugate of an antipsychotic agent and a fatty 35 6. The pharmaceutical composition of claim 5, wherein acid having 12–26 carbons except that the antipsy the fatty acid is an unbranched, naturally occurring fatty chotic agent is not a phenothiazine, or acid. thioxanthene, and wherein the antipsychotic agent is 7. The pharmaceutical composition of claim 6, wherein Selected from the group consisting of: Alentemol the fatty acid has 14-22 carbons. Hydrobromide; Alpertine; Batelapine Maleate; Benzin 40 8. The pharmaceutical composition of claim 6, wherein dopyrine Hydrochloride; Brofoxine; Bromperidol; the fatty acid is docosahexaenoic acid. Bromperidol Decanoate; Butaclamol Hydrochloride; 9. The pharmaceutical composition of any of claims 5-8 Butaperazine; Butaperazine Maleate; Carphenazine further comprising an antipsychotic agent other than the Maleate; Carvotroline Hydrochloride; Cinperene; Cin covalent conjugate. triamide; Clomacran Phosphate; Clopenthixol; Clopi 45 10. The pharmaceutical composition of claim 9, wherein mozide, Clopipazan MeSylate; Cloroperone Hydro the antipsychotic agent other than the covalent conjugate is chloride; Clothiapine; Clothixamide Maleate; Selected from the group consisting of Acetophenazine Male Clozapine, Cyclophenazine Hydrochloride; EtaZolate ate, Alentemol Hydrobromide, Alpertine, AZaperone, Bate Hydrochloride; Fenimide; Flucindole; Flumezapine; lapine Maleate; Benperidol; BenZindopyrine Hydrochloride; Fluspirilene; Flutroline; Gevotroline Hydrochloride; 50 Brofoxine; Bromperidol; Bromperidol Decanoate; Halopemide; Iloperidone; Imidoline Hydrochloride; Butaclamol Hydrochloride; Butaperazine; Butaperazine Lenperone, Mazapertine Succinate; Metiapine; Milen Maleate; Carphenazine Maleate; Carvotroline Hydrochlo perone; Milipertine; Molindone Hydrochloride; Nara ride; Chlorpromazine; Chlorpromazine Hydrochloride; nol Hydrochloride; Neflumozide Hydrochloride; Oca Chlorprothixene; Cinperene; Cintriamide; Clomacran Phos peridone; Olanzapine; Oxiperomide; Penfluridol; 55 phate; Clopenthixol; Clopimozide, Clopipazan MeSylate; Pentiapine Maleate; Pimozide; Pinoxepin Hydrochlo Cloroperone Hydrochloride; Clothiapine; Clothixamide ride; Pipamperone; Piperacetazine; Pipotiazine Palmi Maleate; Clozapine; Cyclophenazine Hydrochloride; Dro tate; Piquindone Hydrochloride; Ouetiapine; Remox peridol; Etazolate Hydrochloride; Fenimide; Flucindole; ipride; Quetiapine Remoxipride Hydrochloride; FlumeZapine, Fluphenazine Decanoate, Fluphenazine Enan Risperidone; Risperadone Rimcazole Hydrochloride; 60 thate; Fluphenazine Hydrochloride; Fluspiperone; Fluspir Seperidol Hydrochloride; Sertindole; Setoperone; Tio ilene; Flutroline; Gevotroline Hydrochloride; Halopemide; peridone Hydrochloride; Tiospirone Hydrochloride; Haloperidol; Haloperidol Decanoate; Iloperidone; Imidoline and Ziprasidone Hydrochloride. Hydrochloride; Lenperone; MaZapertine Succinate; 2. The composition of matter of claim 1, wherein the fatty Mesoridazine; Mesoridazine Besylate; Metiapine; Milenper acid is an unbranched, naturally occurring fatty acid. 65 one; Milipertine; Molindone Hydrochloride; Naranol 3. The composition of matter of claim 2, wherein the fatty Hydrochloride; Neflumozide Hydrochloride; Ocaperidone; acid has 14222 carbons. Olanzapine; Oxiperomide; Penfluridol; Pentiapine Maleate; 5,955,459 15 16 Perphenazine; Pimozide; Pinoxepin Hydrochloride; Pipam Benperidol; BenZindopyrine Hydrochloride; Brofoxine; perone, Piperacetazine, Pipotiazine Palmitate; Piquindone Bromperidol; Bromperidol Decanoate; Butaclamol Hydro Hydrochloride; Prochlorperazine Edisylate; Prochlorpera chloride; Butaperazine; Butaperazine Maleate; Carphena Zine Maleate; Promazine Hydrochloride; Quetiapine; zine Maleate; Carvotroline Hydrochloride; Chlorpromazine; Remoxipride; Remoxipride Hydrochloride; Risperidone; Chlorpromazine Hydrochloride; Chlorprothixene; Cin Rimcazole Hydrochloride; Seperidol Hydrochloride; Sertin perene, Cintriamide; Clomacran Phosphate, Clopenthixol; dole; Setoperone, Spiperone; Thioridazine; Thioridazine Clopimozide; Clopipazan Mesylate; Cloroperone Hydro Hydrochloride; Thiothixene; Thiothixene Hydrochloride; chloride; Clothiapine; Clothixamide Maleate; Clozapine; Tioperidone Hydrochloride; Tiospirone Hydrochloride; Tri Cyclophenazine Hydrochloride; Droperidol; Etazolate fluoperazine Hydrochloride; Trifluperidol; Triflu promazine; Hydrochloride; Fenimide; Flucindole; Flumezapine; Triflupromazine Hydrochloride; and Ziprasidone Hydro Fluphenazine Decanoate, Flu phena Zine Enant hate; chloride. Fluphenazine Hydrochloride; Fluspiperone; Fluspirilene; 11. A kit comprising a package housing Flutroline; Gevotroline Hydrochloride; Halopemide; Halo a container containing the covalent conjugate of any of peridol, Haloperidol Decanoate, Iloperidone, Imidoline claims 1-4, and also housing instructions for adminin 15 Hydrochloride; Lenperone; MaZapertine Succinate; istering to a Subject having a psychotic condition the Mesoridazine; Mesoridazine Besylate; Metiapine; Milenper covalent conjugate. one; Milipertine; Molindone Hydrochloride; Naranol 12. A kit comprising a package housing Hydrochloride; Neflumozide Hydrochloride; Ocaperidone; a first container containing the covalent conjugate of any Olanzapine; Oxiperomide; Penfluridol; Pentiapine Maleate; of claims 1-4, and Perphenazine; Pimozide; Pinoxepin Hydrochloride; Pipam a Second container containing an antipsychotic agent perone, Piperacetazine, Pipotiazine Palmitate; Piquindone other that the covalent conjugate. Hydrochloride; Prochlorperazine Edisylate; Prochlorpera 13. A method for treating a psychotic condition compris Zine Maleate; Promazine Hydrochloride; Quetiapine; ing Remoxipride; Remoxipride Hydrochloride; Risperidone; administering to a Subject in need of Such treatment of a 25 Rimcazole Hydrochloride; Seperidol Hydrochloride; Sertin covalent conjugate of an antipsychotic agent and a fatty dole, Setoperone, Spiperone; Thioridazine; Thioridazine acid having 12–26 carbons, in an amount effective to Hydrochloride; Thiothixene; Thiothixene Hydrochloride; treat the psychotic condition, except that the antipy Tioperidone Hydrochloride; Tiospirone Hydrochloride; Tri chotic agent is not a phenothiazine, butyrophenone or fluoperazine Hydrochloride; Trifluperidol; Triflu promazine; thioxanthene, and wherein the antipsychotic agent is Triflupromazine Hydrochloride; and Ziprasidone Hydro Selected from the group consisting of Alentemol chloride. Hydrobromide; Alpertine; Batelapine Maleate; Benzin 19. The method of claim 13-16 wherein the psychotic dopyrine Hidrochloride; Brofoxine; Bromperidol; Bro condition is Schizophrenia. mperidol Decanoate; Butaclamol Hydrochloride; 20. A method for achieving in a Subject a therapeutic Butaperazine; Butaperazine Maleate; Carphenazine 35 effect longer than that achieved when an equimolar amount Maleate; Carvotroline Hydrochloride; Cinperene; Cin of an antipsychotic agent is administered, comprising triamide; Clomacran Phosphate; Clopenthixol; Clopi administering to a Subject in need of Such treatment a mozide, Clopipazan MeSylate; Cloroperone Hydro covalent conjugate of the antipsychotic agent and a chloride; Clothiapine; Clothixamide Maleate; fatty acid in an amount effective to achieve Said thera Clozapine, Cyclophenazine Hydrochloride; EtaZolate 40 peutic effect, except that the antipsychotic agent is not Hydrochloride; Fenimide; Flucindole; Flumezapine; a phenothiazine, butyrophenone or thioxanthene, and Fluspirilene; Flutroline; Gevotroline Hydrochloride; wherein the antipsychotic agent is Selected from the Halopemide; Iloperidone; Imidoline Hydrochloride; group consisting of: Alentemol Hydrobromide; Alper Lenperone, Mazapertine Succinate; Metiapine; Milen tine; Batelapine Maleate; BenZindopyrine Hydrochlo perone; Milipertine; Molindone Hydrochloride; Nara 45 ride; Brofoxine; Bromperidol; Bromperidol Decanoate; nol Hydrochloride, Neflumozide Hydrochloride; Oca Butaclamol Hydrochloride; Butaperazine; Butapera peridone; Olanzapine; Oxiperomide; Penfluridol; zine Maleate; Carphenazine Maleate; Carvotroline Pentiapine Maleate; Pimozide; Pinoxepin Hydrochlo Hydrochloride; Cinperene; Cintriamide; Clomacran ride; Pipamperone; Piperacetazine; Pipotiazine Palmi Phosphate; Clopenthixol; Clopimozide, Clopipazan tate; Piguindone Hydrochloride, Quetiapine, Remox 50 Mesylate; Cloroperone Hydrochloride; Clothiapine; ipride; Quetiapine Remoxipride Hydrochloride; Clothixamide Maleate; Clozapine; Cyclophenazine Risperidone; Risperadone Rimcazole Hydrochloride; Hydrochloride; Etazolate Hydrochloride; Fenimide; Seperidol Hydrochloride; Sertindole; Setoperone; Tio Flucindole; Flumezapine; Fluspirilene; Flutroline; peridone Hydrochloride; Tiospirone Hydrochloride; Gevotroline Hydrochloride; Halopemide; Iloperidone; and Ziprasidone Hydrochloride. 55 Imidoline Hydrochloride; Lenperone; Mazapertine 14. The method of claim 13, wherein the fatty acid is an Succinate; Metiapine; Milenperone; Milipertine; unbranched, naturally occurring fatty acid. Molindone Hydrochloride; Naranol Hydrochloride; 15. The method of claim 14, wherein the fatty acid has Neflumozide Hydrochloride; Ocaperidone; Olanzap 14-22 carbons. ine; Oxiperomide; Penfluridol; Pentiapine Maleate; 16. The method of claim 14, wherein the fatty acid is 60 Pimozide; Pinoxepin Hydrochloride; Pipamperone; docosahexaenoic acid. Piperacetazine; Pipotiazine Palmitate; Piquindone 17. The method of any of claims 13-16 further compris Hydrochloride, Quetiapine, Remoxipride; Quetiapine ing an antipsychotic agent other than the covalent conjugate. Remoxipride Hydrochloride; Risperidone; Rispera 18. The method of claim 17, wherein the antipsychotic done Rimcazole Hydrochloride; Seperidol Hydrochlo agent other than the covalent conjugate is Selected from the 65 ride; Sertindole; Setoperone; Tioperidone Hydrochlo group consisting of Acetophenazine Maleate; Alentemol ride; Tiospirone Hydrochloride; and Ziprasidone Hydrobrornide, Alpertine, AZaperone; Batelapine Maleate; Hydrochloride. 5,955,459 17 18 21. The method of claim 20, wherein the fatty acid is an 28. The method of claim 24-27, wherein the covalent unbranched, naturally occurring fatty acid. conjugate is administered not more than once per day. 22. The method of claim 21, wherein the fatty acid has 29. A method for reducing the amount of antipsychotic 14-22 carbons. agent administered to a Subject having a psychotic condition 23. The method of claim 21, wherein the fatty acid is 5 treatable by said antipsychotic agent, comprising docosahexaenoic acid. administering a covalent conjugate of Said antipsychotic 24. A method for decreasing the number of daily doses required to achieve in a Subject a therapeutic effect equiva agent and a fatty acid having 12–26 carbons to Said lent to that achieved when an equimolar amount of antip Subject at a molar dose at least 50% below the dose of Sychotic agent is administered comprising the unconjugated antipsychotic agent necessary to administering to a Subject in need of Such treatment a achieve the same therapeutic effect as is achieved with covalent conjugate of the antipsychotic agent and a Said conjugate, and wherein the antipsychotic agent is fatty acid in an amount effective to achieve Said thera Selected from the group consisting of: Alentemol peutic effect, and wherein the antipsychotic agent is Hydrobromide; Alpertine; Batelapine Maleate; Benzin Selected from the group consisting of: Alentemol 15 dopyrine Hydrochloride; Brofoxine; Bromperidol; Hydrobromide; Alpertine; Batelapine Maleate; Benzin Bromperidol Decanoate; Butaclamol Hydrochloride; dopyrine Hydrochloride, Brofoxine; Bromperidol; Bro Butaperazine; Butaperazine Maleate; Carphenazine mperidol Decanoate; Butaclamol Hydrochloride; Maleate; Carvotroline Hydrochloride; Cinperene; Cin Butaperazine; Butaperazine Maleate; Carphenazine triamide; Clomacran Phosphate; Clopenthixol; Clopi Maleate; Carvotroline Hydrochloride; Cinperene; Cin- 20 mozide, Clopipazan MeSylate; Cloroperone Hydro triamide; Clomacran Phosphate; Clopenthixol; Clopi- chloride; Clothiapine; Clothixamide Maleate; mozide, Clopipazan MeSylate; Cloroperone Hydro- Clozapine, Cyclophenazine Hydrochloride; EtaZolate chloride; Clothiapine; Clothixamide Maleate; Hydrochloride; Fenimide; Flucindole; Flumezapine; Clozapine, Cyclophenazine Hydrochloride; EtaZolate Fluspirilene; Flutroline; Gevotroline Hydrochloride; Hydrochloride; Fenimide; Flucindole; Flumezapine; 25 Halopemide; Iloperidone; Imidoline Hydrochloride; Fluspirilene; Flutroline; Gevotroline Hydrochloride; Lenperone, Mazapertine Succinate; Metiapine, Milen Halopemide; Iloperidone; Imidoline Hydrochloride; perone; Milipertine; Molindone Hydrochloride; Nara Lenperone, Mazapertine Succinate; Metiapine; Milen- nol Hydrochloride; Neflumozide Hydrochloride; Oca perone; Milipertine; Molindone Hydrochloride; Nara- peridone; Olanzapine; Oxiperomide; Penfluridol; nol Hydrochloride; Neflumozide Hydrochloride; Oca- 30 Pentiapine Maleate; Pimozide; Pinoxepin Hydrochlo peridone; Olanzapine; Oxiperomide; Penfluridol; ride; Pipamperone; Piperacetazine; Pipotiazine Palmi Pentiapine Maleate; Pimozide; Pinoxepin Hydrochlo- tate; Piquindone Hydrochloride; Quetiapine; Remox ride; Pipamperone, Piperacetazine, Pipotiazine Palmi- ipride; Quetiapine Remoxipride Hydrochloride; tate; Piguindone Hydrochloride, Quetiapine, Remox- Risperidone; Risperadone Rimcazole Hydrochloride; ipride; Quetiapine Remoxipride Hydrochloride; 35 Seperidol Hydrochloride; Sertindole; Setoperone; Tio Risperidone; Risperadone Rimcazole Hydrochloride; peridone Hydrochloride; Tiospirone Hydrochloride; Seperidol Hydrochloride; Sertindole; Setoperone; Tio- and Ziprasidone Hydrochloride. peridone Hydrochloride; Tiospirone Hydrochloride; 30. The method of claim 29, wherein the fatty acid is an and Ziprasidone Hydrochloride. unbranched, naturally occurring fatty acid. 25. The method of claim 24, wherein the fatty acid is an 40 31. The method of claim 30, wherein the fatty acid has unbranched, naturally occurring fatty acid. 14-22 carbons. 26. The method of claim 25, wherein the fatty acid has 32. The method of claim 30, wherein the fatty acid is 14-22 carbons. docosahexaenoic acid. 27. The method of claim 25, wherein the fatty acid is docosahexaenoic acid. k . . . .