standard drug therapy for psychosis and other dopamine receptor dysfunctional involves continuous treatment with regular doses of dopamine receptor antagonists . while this therapy is often at least partially effective for the treatment of the positive symptoms , namely psychosis , it fails to address other aspects of the illness , namely the negative symptoms , cognition , attention and concentration . additionally , all anti - dopaminergic drugs , currently available , have certain significant side effects , including parkinsonism , akathisia , and tardive dyskinesia . at present , there are research treatments that involve administration of dopamine agonists . as mentioned above , this treatment suffers from efficacy tolerance . therefore , it is clear there is a need for effective antipsychotics that treat both positive , cognitive , and negative symptoms of the disorder without the commonly reported motor side effects . the object of the invention is to allow long term treatment of a disease of the central nervous system by receptor agonists , without development of tolerance to the treatment . by long term treatment or therapy , it is meant treatment with no predetermined end point , such as might continue for weeks or months , or even for the life of the patient . the basis of the current invention was the insight that lowering the agonist intrinsic activity ( ia ) might be a mechanism to decrease efficacy tolerance to the drug . it has been recently discovered that mixtures of a full antagonist with a partial agonist , each for the same neurotransmitter system , can result in a reduced ia , partial agonist . in preliminary studies , the inventors discovered that partial agonists with lower ia have a longer duration of clinical antipsychotic action . based on this effect , the goal was to expand the duration of effect of a desirable dopamine agonist treatment for schizophrenia and convert it into a therapeutically viable treatment by reducing the agonist ia through combining it with a very low dose of a full dopamine antagonist . in initial experiments , the agonist used was (−)- 3ppp and the antagonist used was haloperidol . the results of these experiments , discussed in detail below , confirmed the basic premise , that a low dose of an antagonist delivered in combination with a dose of partial agonist can preserve the anti - psychotic activity and lengthen our indefinitely the therapeutically beneficial properties of the agonist . the present invention is the first to knowingly combine an agonist with varying concentrations of its own receptor &# 39 ; s antagonist . this combination has the effect of modifying the intrinsic activity of the agonist for treatment of a human disease . although the preferred combination of drugs targets the dopamine receptor , these principles and strategies would be similarly applicable to other cns transmitter systems and disease treatments . the present invention represents a pharmacologic therapy that is vastly superior to any that are currently applied in the clinical setting or even contemplated by the literature . the advantage of such combination drug therapy in the field of schizophrenia is the equivalent treatment of positive psychotic symptoms , without any motor or dysphoric side effects , no elevation of plasma prolactin levels , and with potential for the treatment of negative and cognitive symptoms of this illness . negative symptoms , when untreated in schizophrenia , markedly impair psychosocial recovery and rehabilitation . no current antipsychotics effectively treat negative symptoms , making the identification of an effective agent imperative . the motor side effects of current antipsychotic treatments are extremely painful and bothersome to the patient . these side effects also reduce compliance and are consequently associated with drug discontinuation and illness relapse . so antipsychotic treatments without motor side effects are important and clinically relevant . moreover , the disclosed drug combination can reduce the long term incidence of the delayed neuroleptic - induced motor side effect called , tardive dyskinesia . the medical and legal implications of this possibility are considerable . clearly , the potential advantages of this treatment over other currently available treatments are great . because the treatment for schizophrenia is a receptor agonist , this treatment strategy avoids dopamine - antagonist - induced side effects : these include drug induced parkinsonism , akathisia , and tardive dyskinesia ; they can also include neuroleptic - induced dysphoria , negative symptoms , and cognitive impairment . moreover , the drug combination of the present invention can serve as a primary treatment for negative symptoms in schizophrenia and for cognitive dysfunction in the illness . in other conditions , especially affective psychosis ( mania and psychotic depression ), the drug therapy of the instant invention can provide effective treatment without any tardive dyskinesia risk . the limited success of antipsychotic treatments in the non - schizophrenic psychoses is in large part due to neuroleptic - induced side effects , which could be avoided with this combination . as the molecular structures of the different dopamine ( da ) receptors has been defined over the last decade ( gingrich , j . a ., caron , m . g . : annual review of neuroscience , ( 1993 ) 16 : 299 - 321 . jarvie , k . r ., caron , m . g . : advances in neurology , ( 1993 ) 60 : 325 - 333 . ), the action of drugs at the different receptor sites has become increasingly clear . multiple da receptors exist , as multiple targets for drug action . the structure of all da receptors is a g protein - coupled receptor , where the seven transmembrane - spanning sites are arranged in a donut - like shape in the membrane . how a drug interacts with a receptor , to deliver its action , is becoming increasingly clear . the sites where da electrostatically binds to the critical amino acids to effect a change in protein conformation are known : asp 3 , ser 5 and ser 5 . agonists affect the protein conformational change at the d 2 receptor with different potencies and consequently deliver different potency signals to the cell . antagonists merely cap the top of this receptor complex , without producing any effect on the receptor structure at all ( tamminga , c . a ., dahl , s . g . ( 1994 ) am . j . psychiatry , 151 : 4 .). the use of a receptor agonist is different in several practical respects from a receptor antagonist . since a receptor antagonist blocks all ( or nearly all ) transmission at that receptor , any drug - induced alterations in that receptor are not an immediate issue for the nature of clinical drug action . however , an agonist changes the state of the receptor by reason of its receptor activation , producing receptor desensitization . if continued therapeutic stimulation of the receptor is desired , special techniques are necessary to avoid desensitization and preserve activity . repeated agonist stimulation of a receptor produces desensitization and ultimate insensitivity of that receptor to the stimulus . this is physiologic , and occurs in all brain , g protein systems . the details of the molecular events of receptor desensitization are currently being studied ( gingrich , j . a ., caron , m . g . ( 1993 ) annual review of neuroscience , 16 : 299 - 321 ; jarvie , k . r ., caron , m . g . ( 1993 ) advances in neurology , 60 : 325 - 333 ; caron , m . g . ( 1994 ): in dopamine receptor subtypes in neurological and psychiatric diseases , brooklodge , kalamazoo , mich .). agonist stimulation at any g protein - coupled recognition site produces phosphorylation of amino acids near the distal end of the third intracytoplasmic loop . this phosphorylation putatively facilitates the attraction between the recognition site and the effector protein of the receptor and is responsible for receptor desensitization , then receptor involution , and finally actual intracellular breakdown of the receptor protein ( caron , m . g . ( 1994 ): in dopamine receptor subtypes in neurological and psychiatric diseases , brooklodge , kalamazoo , mich .). there are known medical diseases linked to abnormalities of receptor desensitization , suggesting the physiologic and pathophysiologic importance of this process ( lefkowitz , r . j . ( 1993 ) nature , 365 : 603 - 604 ,.). again , while not wishing to be bound by theory , tolerance to the clinical therapeutic actions of (−)- 3ppp is most likely based on this desensitization response to agonist stimulation . partial agonists at any receptor are those drugs which have a strong affinity for the receptor but limited intrinsic activity . partial agonists are attracted to a receptor and bind to it , with an affinity similar to the natural ligand , but , once bound , have a lesser activity ( ariens , e . j . ( 1954 ) arch . int . pharmacodyn . ther ., 99 : 32 - 49 , kenakin , t . p . ( 1993 ) pharmacologic analysis of drug - receptor interaction . raven press , new york .). depending on the state of occupancy of that receptor , and the drug &# 39 ; s intrinsic activity , these partial agonists can have an overall antagonist or agonist action on neurotransmission at that synapse . partial agonists can have a high level of intrinsic activity ( approaching the 100 % activity of the natural agonist ) and act much like a full agonist ; or , they can have a low level of intrinsic activity ( perhaps of 5 % - 10 %) and act nearly like an antagonist . in between , partial agonists have widely varying levels of intrinsic activity , and differing behavioral actions . the resultant pharmacologic action of these medium - intrinsic activity agonists depends on the state of the target system . over the last twenty years , considerable work has been done testing dopamine agonists in schizophrenia ( tamminga c a , schaffer m h , smith r c , davis j m ( 1978 ): science 200 : 567 - 568 ; tamminga c a , gotts m d , thaker g k , alphs l d , foster n l ( 1986 ): arch gen psychiatry 43 : 398 - 402 ; corsini , g . u ., delzompo , m ., manconi , s ., cianchetti , c ., mangoni , a ., gessa , g . l . : ( 1977 ) adv biochem psychopharmacol , 16 : 645 - 648 ; corsini , g . u ., pitzalis , g . f ., bernardi , f ., bocchetta , a ., del zompo , m . ( 1981 ) neuropharnacol , 20 : 1309 - 1313 ; ferrier , e . c ., johnstone , e . c ., crow , t . j . ( 1984 ) br j psychiatry , 144 : 341 - 348 ; but only recently have partial agonists been available for clinical study ( olbrich , r ., schanz , h . : ( 1988 ) pharmacopsychiat ., 21 : 389 - 390 , winckler , p ., bartels , m . : psychiatric university hospital tuebingen ( frg ); benkert , o ., grunder , g . wetzel , h . : ( 1992 ) pharmacopsychiatry , 25 : 6 ; murasaki , m ., miura , s ., ishigooka , j ., ishii , y ., takahashi , a ., fukuyama , y . : ( 1988 ) prog . neuro - psychopharmacol . & amp ; biol . psychiat ., 12 : 793 - 802 ; kiuchi , k ., hirata , y ., minami , m ., nagatsu , t . : ( 1988 ) life sciences , 42 : 343 - 349 .). of the partial agonists studied recently , (−)- 3ppp is the only one which is relatively selective for dopamine receptors and lacks activity at other monoamine receptors ( hjorth , s ., carlsson , a ., clark , d ., svensson , k ., wikstrom , h ., sanchez , d ., lindberg , p ., hacksell , u ., arvidsson , l . e ., johansson , a ., nilsson , j . l . g . ( 1983 ) psychopharmacol ., 81 : 89 - 99 ). until recently , attempts to identify additional agonists as antipsychotic have not yielded good results . it is possible that the failures result from the broad monoaminergic action of these non - aporphine dopamine agonists and their high level of intrinsic activity . as discussed above , intrinsic activity ( ia ) at the dopamine receptor refers to the magnitude of agonist action of a drug delivered at its receptor , not the strength with which that drug binds to its receptor . subsequently , we have identified two other dopamine agonists , n - propylnorapomorphine ( npa ) ( tamminga c a , gotts m d , thaker g k , alphs l d , foster n l ( 1986 ): arch gen psychiatry 43 : 398 - 402 .) and (−) 3 -( 3 - hydroxyphenyl )- n - n - propylpiperidine [(−)- 3ppp )] ( lahti a c , weiler m a , corey p k , lahti r a , carlsson a , tamminga c a ( 1997 ): in press , biological psychiatry . ) as drugs demonstrating antipsychotic properties . by better understanding the relationship between intrinsic activity and receptor manipulation , it will be possible to more efficiently design and discover novel , unique therapeutic agents that can treat disorders associated with transmitter malfunction . in the past , an agent determined to have too high of an intrinsic activity for a particular therapy was discarded , forcing the scientist to go back to the “ drawing board ” to design another drug . now , using the information and techniques disclosed herein , it will be possible to reevaluate those agents determined to be ineffective or inefficient from a therapeutic perspective . many transmitter affecting agents previously rejected , having been tested only in as a single agent drug therapy , may find utility when used in combination with counter - agents of same neurotransmitter system . while the invention has been described in detail , and with reference to specific embodiments thereof , it will be apparent to one with ordinary skill in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof . it is clear that this drug combination could also be applied to other mental or motor conditions , including affective and anxiety disorders ( mania or depression ), psychosis of the elderly with or without dementia , and in episodic axis ii psychotic conditions like multiple personality disorders and borderline conditions ( hardman , j ., gilman , a ., and limbird , l , ( 1995 ). chapters 18 , 22 , 24 , goodman and gilman &# 39 ; s the pharmaceutical basis of therapeutics , mcgraw hill co ., new york ). because of the very low risk ( if any ) of tardive dyskinesia with this treatment , it would reduce the medical and legal risk associated with current antipsychotic treatments especially as those are manifest in non - schizophrenic psychosis where the incidence of tardive dyskinesia is greater . moreover , this treatment could also be applied in neurologic diseases or disorders , including motor disorders , where dopamine dysfunction is involved and neuroleptics or dopamine agonists are now used . such diseases or disorder include but are not limited to , for example in tourette &# 39 ; s disease , huntington &# 39 ; s chorea , parkinson &# 39 ; s disease , tardive dyskinesia , obsessive - compulsive disorder . a current treatment for parkinson &# 39 ; s disease is carbidopa - levodopa , such as sinemet ®, which is dosed at 300 - 10000 mg bid . could be combined with a dopamine antagonist such as holoperidol to prevent tolerance or side effects . likewise , this treatment could be used to treat disorders currently treated with antipsychotic drugs for clinical reasons . such disorders include but are not limited to neurodevelopmental disorders and autism , mental retardation , subclinical or latent psychosis , schizophrenia comorbid with substance abuse , substance abuse alone , dementia in the elderly with behavioral disturbance , and l - dopa - induced hallucinations in parkinson &# 39 ; s disease . patients with such diseases or disorders currently being treated with antipsychotic drugs would especially benefit from the “ no - motor - side - effect ” profile of this drug combination . furthermore , as the biochemical principles are essentially the same for most g protein receptors , one could utilize the teachings herein to provide a pharmacologic therapy for central nervous disorders associated with the dysfunction of other transmitters , such as serotonin , norepinephrine , or acetyl choline . a specific pharmacologic treatment or therapy would involve the administration of a full or partial receptor agonist in combination with a receptor antagonist , the combination providing an agonist with reduced intrinsic activity . for drugs for which specific doses are not given in the examples , the general dosing schedule would be to dose the receptor antagonist at approximately one tenth normal dose , and the agonist at normal dose levels , starting at a low dose and increasing as would be normal in clinical practice . it is within the scope of the invention to formulate or compound any single receptor agonist or receptor antagonist or combination thereof so as to provide a pharmaceutically acceptable dosage form . such a dosage form could comprise an oral or parenteral dosage . the drug could be administered as a single dose or multiple doses , containing single or more than one active drug . the dose range for each component is within the competence of one skilled in the art to determine for each patent . the skilled practitioner would consider the recommended dose of the drug , the condition of the patent , and the tractability of the symptoms to therapy . the skilled practitioner would adjust the dose over a period of days to weeks to achieve maximum efficacy . practitioners in psychiatric and neurologic practice routinely perform such dose adjustment as part of normal practice . all publications cited herein are incorporated by reference in their entirety . cl examples the data herein can predict and help select optimal agonist intrinsic activity for clinical testing for anti - psychotic activity , duration of therapeutic action , and side effects . relative dosages of partial agonist and full antagonist can be determined using routine experimentation . however , the following examples are provided for illustrative purposes only , and are in no way intended to limit the scope of the present invention . it is clear that there is a relationship between agonist therapy and tardive dyskinesia inhibition . studies of partial dopamine agonist , (−)- 3ppp , were extended to additional syndromes sensitive to anti - dopaminergic strategies . tardive dyskinesia ( td ) is the hyperkinetic involuntary movement disorder , which occurs in the context of chronic neuroleptic treatment . it occurs at an incidence rate of 5 % per treatment year , determined prospectively ( kane j m , in : bloom f e and kupfer d j ( eds ) psychopharmacology : the fourth generation of progress . raven press , new york , pp . 1485 - 1495 , 1995 .). since overall prevalence rates are 20 %- 60 %, the expectation is that the incidence rate will plateau after some number of treatment years , but the inflection point is not yet clear . while the etiology of td is clear ( i . e . chronic neuroleptic administration ), the exact pathophysiology , necessary to target prophylaxis or treatment , is unknown . the clinical pharmacology of td suggests the utility of drugs , which decrease da - mediated neurotransmission ( e . g . partial da agonists ) or gaba agonists as therapeutically effective . some data from human ( thaker g k , tamminga c a , alphs l d , lafferman j , ferraro t n , hare t a : ( 1987 ) arch . gen . psychiatry 44 : 522 - 529 .) and from animal studies ( kaneda h , shirakawa o , dale j , goodman l , bachus s e , tamminga c a : ( 1992 ) eur j pharmacol 212 : 43 - 49 ) both suggest that dyskinesia can be reversed in td . the clinical pharmacology of dopamine system stimulation and inhibition in tardive dyskinesia is surprisingly similar to schizophrenia . dopaminergic stimulation with potent indirect agonists characteristically worsen tardive dyskinesia . d - amphetamine clearly worsens dyskinesia in a dose - dependent fashion ; bromocriptine probably worsens dyskinesia even though not significantly ( tamminga c a , chase t n : ( 1980 ) arch neurol 37 : 204 - 205 ). as in psychosis , apomorphine paradoxically improves tardive dyskinesia , both significantly and substantially ( tamminga c a , schaffer m h , smith r c , davis j m ( 1978 ): science 200 : 567 - 568 .). cf25397 ( a lower affinity ergot dopamine agonist ) and piribedil ( a full da agonist ) modestly improved dyskinetic symptoms in td ( table 1 ) ( tamminga , c . a . : ergot compounds and brain function . in : m . goldstein et al . ( eds .) neuroendocrine and neuropsychiatric aspects . raven press , new york , 1980 .). moreover , (−)- 3ppp improves l - dopa - induced dyskinesia in parkinson &# 39 ; s disease , a motor condition in some ways similar to td . in the course of studying dopamine agonists for the treatment of psychosis , assayed dopamine agonists to determine tolerance limits . intrinsic activity is determined using a functional assay which involves an agonist - induced release of [ 3 h ] arachidonic acid from cho cells stably transfected with the d 2 receptor ( lahti , r . a ., figur , l . m ., piercey , m . f ., ruppel , p . l ., evans , d . l . : ( 1992 ) mol . pharmacol ., 42 : 432 - 438 ). cloned dopamine receptors are used to quantify intrinsic activity , with the intrinsic activity estimates calculated using the ratio of the compounds affinity at the low - affinity agonist state to its affinity for the high affinity agonist state . first , in examining the efficacy tolerance of npa , a full dopamine agonist ( ia = 90 %), tolerance was observed after 24 hours . next , the efficacy tolerance of (−)- 3ppp , the partial dopamine agonist ( ia = 40 %), produced a longer efficacy , lasting up to 7 days . the observation that lower intrinsic activity seemed to relate to longer therapeutic effect gave an indication as to how to extend the therapeutic efficacy of partial agonists like (−)- 3ppp and block tolerance . this initial observation in conjunction with the known fact that mixtures of full antagonists with partial agonists , each for the same neurotransmitter system , results in reduced ia partial agonist led the inventors to perform the subsequent experiments described herein to confirm the theory . many potential compounds were screened in this model to find drugs with favorable partial agonist characteristics for treating psychosis . these characteristics include : an activity restricted to the dopamine d 2 system , with little affinity for the d 1a or serotonin 5ht 1a or 5ht 2a receptors , and an intrinsic activity between 18 % and 35 %. examples of data generated in the evaluation of a number of compounds are presented in the following three tables ( tables 2 - 4 ). [ 0039 ] table 4 summary of affinities and intrinsic activities of dopamine and (−)- 3 - ppp for hd 21 and hd 4 - type receptors dopamine (−) 3 - ppp intrinsic intrinsic receptor type k i ( nm ) # activity % k i ( nm ) # activity % hd 3 4 . 5 100 % 30 . 9 46 % hd 42 6 . 0 100 % 30 . 9 73 % hd 44 2 . 7 100 % 13 . 2 97 % hd 47 2 . 4 100 % 14 . 3 98 % it is possible to experimentally predict the level of ia of an agonist which will be devoid of any receptor down - regulating properties . the basic premise of the present invention is that reduction of the agonist ia will tend to reduce tolerance , and ultimately obliterate it entirely . tolerance likely occurs because of receptor desensitization in vivo . thus , laboratory studies of drug concentrations associated with no desensitization help to rationally to select and test partial dopamine agonists and / or their combinations . the preferred technique for assaying the dopamine receptor sensitivity and regulatory effects was used . specifically , it has been shown that chronic treatment of cho cells expressing the cloned 5ht 1a receptor with a 5ht 1a agonist results in the down - regulation and functional desensitization of the 5ht 1a receptor ( rotondo a , nielsen d a , nakhai b , hulihan - giblin b , bolos a , goldman d . ( 1997 ). neuropsychopharmacolgy 17 : 18 - 26 .). since the d 2 receptor is similar to the 5ht 1a receptor in that it is coupled to g 1 , chronic d 2 agonist treatment of cho cells was used in a parallel technique to study receptor down - regulation . the full agonist u - 86170 , which is stable in aqueous solutions was used , in various doses to desensitize the cho cell containing d 2 receptor , in comparison to dopamine . once the “ ideal ” intrinsic activity is arrived at , it can be used to study the agonist (−)- 3ppp alone and in combination with varying doses of haloperidol or clozapine to determine the relationship between ia and d 2 receptor desensitization . combining a receptor agonist with its own antagonist can reduce the agonist &# 39 ; s intrinsic activity . in the laboratory , this was shown for (−)- 3 - ppp . it was also found haloperidol can reduce the intrinsic activity of (−) 3 - ppp from 36 %, when it is tested without haloperidol , to approximately 20 % intrinsic activity in the presence of 1000 nm haloperidol , fig1 . thus a 30 : 1 ratio of (−)- 3 - ppp to haloperidol would produce a designed mix with an intrinsic activity of almost one - half that of the partial agonist alone . these data confirm the idea that combining (−)- 3 - ppp with low concentrations of a full antagonist , like haloperidol , will reduce its functional intrinsic activity . (−)- 3ppp was combined with varying concentrations of haloperidol and demonstrated a linear reduction in the intrinsic activity of (−)- 3 - ppp with increasing concentrations of haloperidol ( fig1 ). after demonstrating the antipsychotic action of (−)- 3 - ppp , but showing that it has only a duration of approximately one week with continuous dosing ( lahti a c , weiler m a , corey p k , lahti r a , carlsson a , tamminga c a ( 1997 ): in press , biological psychiatry . ), a combination of (−)- 3 - ppp and a low dose of a known dopamine receptor antagonist , haloperidol was tested . this combination was designed to produce a lower ia (−)- 3ppp , and thereby prolonging its antipsychotic activity . to test this , actively psychotic schizophrenic persons were tested with (−)- 3ppp ( 300 mg bid ) plus haloperidol ( 1 mg bid ), compared to the haloperidol alone . this dose of haloperidol may have delivered a measurable antipsychotic effect . however , the antipsychotic effect of (−)- 3ppp was apparent and was present in week one and it extended longer for the entire two week period of the trial without evidence of tolerance . ( table 5 ). these data support the basic premise that combination of a low dose of antagonist with (−)- 3ppp will preserve its antipsychotic activity and lengthen out perhaps indefinitely the action (−)- 3ppp . a preliminary clinical trial co - administration of receptor agonist and antagonist is being conducted . the efficacy of treatment is further tested by comparing placebo treated to drug treated groups . the study is designed to demonstrate that co administration of the dopamine antagonist , haloperidol with the partial receptor agonist , (−)- 3 - ppp reduces symptoms of psychosis . study design : patients are entered into the study based of psychiatric evaluation based on at least weekly ratings . after being entered into the study patients are randomly assigned into experimental or control groups . the study is conducted double blind so that neither patients nor physician are aware of which group patients are entered into . patients are treated with haloperidol 0 . 5 mg b . i . d , for two weeks to establish stable conditions . patients are then treated with the partial dopamine receptor agonist , (−)- 3 - ppp , at a dose between 300 and 600 mg bid . the dose of (−)- 3 - ppp is corrected over the first week depending on the evaluation of the psychiatrist . optimal dose levels are often approximately 450 mg bid . patients receive haloperidol at a constant dose throughout . control groups receive haloperidol and a placebo tablet in place (−)- 3 - ppp . groups are maintained in treatment for 4 - 6 weeks , with continued weekly rating . a minimum of ten patients will be randomized to each group . patients will be evaluated weekly by a rating system to measure improvement . a protein with a distinctive tertiary structure , often membrane bound , with specialized areas for recognizing particular signaling molecules on a ligand ; when a receptor complexes with its ligand the interaction alters subsequent cellular properties ( electrophysical , biochemical , and / or molecular ). a signaling substance within nervous system which transmits encoded signals to neurons at a specialized receptor site . a signaling chemical which , when coupled to its specific receptor , effects a characteristic cellular action . a chemical substance which couples to a specific receptor without producing an action except to block other substances from that receptor . a cell - surface g protein coupled receptor protein which recognizes dopamnine as its natural neurotransmitter and shows a high affinity for such ligands as reclopride and haloperidol but not sch 23390 ; highly concentrated in basel ganglia . a state of reality distortion where the psychotic person has perceptual experiences not supported by reality , imagines malice falsely and / or has involuntary , disconnected , illogical thoughts .
dopamine receptor antagonists are commonly prescribed for the treatment of schizophrenia and psychosis . while they are effective antipsychotics , they fail to treat other aspects of the disorder and have severe side effects , ranging from parkinsonism , acute motor side effects , akasthisia , dysphoria , and tardive dyskinesia . dopamine agonist drug treatments are effective in treating both positive and negative symptoms without the common side effects . unfortunately , dopamine agonists suffer from efficacy tolerance , the time limited effect on the order of 1 - 7 days . thus , despite the partial effectiveness of current treatments , pressing need exists for new treatments . the combination drug therapy described herein meets this need . specifically , the invention involves the use of small doses of dopamine receptor antagonists to reduce the intrinsic activity of a partial agonist , thereby reversing the agonist - induced tolerance commonly reported with agonist therapy alone .