Jefferson Journal of Psychiatry

Volume 7 Issue 1 Article 4

January 1989

Mechanisms and Therapeutic Implications of Neuroleptic Atypicality

Daniel C. Javitt, MD Albert Einstein School of Medicine

Follow this and additional works at: https://jdc.jefferson.edu/jeffjpsychiatry

Part of the Psychiatry Commons Let us know how access to this document benefits ouy

Recommended Citation Javitt, MD, Daniel C. (1989) "Mechanisms and Therapeutic Implications of Neuroleptic Atypicality," Jefferson Journal of Psychiatry: Vol. 7 : Iss. 1 , Article 4. DOI: https://doi.org/10.29046/JJP.007.1.001 Available at: https://jdc.jefferson.edu/jeffjpsychiatry/vol7/iss1/4

This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Jefferson Journal of Psychiatry by an authorized administrator of the Jefferson Digital Commons. For more information, please contact: [email protected]. Mechanisms and Therapeutic Implications ofNeuroleptic Atypicality

Daniel C. Javitt, M.D .

PRECIS

Neuroleptics have proven effective for the overall treatment ofschizophre­ nia . The neuroleptic therapy of schizophrenia, however, has been limited by tardive dyskinesia and by the relative inability of neuroleptics to ameliorate th e negative symptoms of schizophrenia. Intensive research has been conducted to identify atypical neuroleptics which would not cause TO and which would ha ve relatively greater efficacy in treating negative symptoms. Based upon animal models of T D and negative symptoms, four neuroleptics have been identified which may have these properties: c1ozapine, thioridazine, sulpiride, and molin­ done. Clinical studies of TD suggest that these four potentially atypical agents may have lower dyskinetic potential than typical neuroleptics. Additionally, clinical studies of negative symptoms suggest that molindone and sulpiride, bu t not clozapine or thioridazine may preferentially treat depressive-like negative schizophrenic symptomatology. The atypical effects of c1ozapine, thioridazine, sulpiride and molindone, suggest that they may have a distinct place in th e pharmacotherapy of schizophrenia.

INTRODUCTION

Since their d iscovery in the mid-1950s, neuroleptic drugs have proven to be safe and effective treatments for schizophrenia. Schizophrenic subjects treated with neuroleptics have been shown to have improved overall functioning and a decreased need for hospitalization versus non-treated controls. The pharmacotherapy ofschizophrenia with neuroleptics, however, has proven to be limited by at least two factors. First, neuroleptics increase the rate at which schizophrenic patients develop the long-term potentially irreversible and inca­ pacitating movement disorder, tardive dyskinesia (TO). Second, neuroleptics have proven relatively ineffective in treating the negative symptoms of schizo­ phrenia (e.g. blunted affect, poverty of speech and of ideation) (1,2) and ma y induce akinetic symptoms which closely resemble the negative schizophrenic symptoms (3,4). Intensive research has been conducted over the past three decades on both a basic scie nce and a clinical level to determine whether or not these two lim itations are inevitable concomitants of neuroleptic therapy. Basic studies using animal models of TO and negative symptoms now suggest that several agents do behave differently from traditional neuroleptics (e.g. chlor­ prom azine, haloperidol) an d may indeed possess atypical clinical properties

3

( 4 JEFFERSON JOURNAL OF PSYCHIA TRY including a relatively decreased dyskinetogenic potential and/ or a relatively increased efficacy in treating negative symptoms. Four such potentially atypical agents have been identified. Clozapine, a compound of th e dibenzodiazepine class, has been the best studied and is considered th e prototype atypical neuroleptic. Long-term clinical studies have suggested that clozapine has low to absent dyskinetogenic potential. Clozapine, however, remains available in th is country only on an experimental basis because of associated agranulocyto sis. Thioridazine, a widely used neuroleptic of the piperidine phenothiazine class, appears to have c1ozapine-like effects in basic models ofTD although to a more limited extent. Detailed clinical studies have not been conducted th at woul d allow a determination of the dyskinetogenic potential of thioridazine. Cases of TD presumably related to thioridazine treatment have been reported and th e possible decreased dyskinetogenic potential of thioridazine has been much debated (5,6). Sulpiride, a substituted benzamide, and molindone, an indolic derivative, are other neuroleptics with novel chemical structures. These agents, at least in some dose ranges, behave similarly to clozapine in basic models ofTD. While definitive clinical studies have yet to be performed for th ese agents, studies using masking paradigms suggest that these agents also may have decreased dyskinetogenic potential compared with traditional neuroleptics. Sulpiride and molindone behave differently from traditional neuroleptics in animal models of negative symptoms as well, suggesting that th ey may also have improved efficacy in treating negative symptoms.

BASIC STUDIES

The role of dopaminergic hyperactivity in schizophrenic pathophysio logy has now been well established. Agents which increase brain dopaminergic transmission worsen overall schizophrenic symptomatology. The poten cy with which neuroleptic agents ameliorate schizophrenic symptoms correlat es with their potency in blocking dopaminergic transmission at D2 type dopamine receptors (7,8). Less well established, however, is the role of the various brain dopaminergic systems in contributing to schizophrenic pathophysiology and the clinical response to neuroleptics. Three separate dopaminergic systems have been identified in forebrain. Two of these, the mesocortical and mesolimbic systems arise from the midbrain ventral tegmental area (area Al 0) and innervate the neocortex (e.g. frontal cortex, cingulate cortex) and limbic system (e.g. nucleus accumbens) respectively. The third arises from the substantia nigra (area A9) and innervates the neostriatum. The me socortical and mesolimbic systems are thought to subserve cognition and affective regulation whil e th e nigrostriatal system, which has been implicated in th e pathophysiology of Parkinson's disease (9) and Huntington's chorea (10), is thought to be involved mainly with regulation of brain motoric systems. The th erapeutic ac tions of neuroleptics and their behavioral side effects ma y result primarily from th eir actions in the mesolimbic and mesocortical systems while the d yskinet ogenic MECHANISMS AND T HERAPEUTIC IMPLICATIONS 5 effects of neuroleptics are likel y to be mediated by th ei r actions on the nigrostriatal system (7,8). As a result, agents whi ch selec tively spare th e nigro­ striatal system should have a relatively decreased risk of inducin g T D. Several model systems have been used in an attempt to measure th e effec ts of neurolep­ tics on th e mesocortical and mesolimbic systems versus th eir effects on the nigrostriatal system. Three of th ese paradigms in particul ar have gained widespread acceptance (Table I). Studies using th ese paradi gms suggest that the proposed atypical agents c1ozapine, thioridazin e , sulpiride, an d molindone induce less inhibition of nigrostriatal dopaminergic transm ission than tradi­ tional agents. These agents, therefore, might have a relativel y decreased risk for inducing motoric side effects and, in particular,T D.

Behavioral Supersensitivity

The first model of TD is bas ed upon th e observation tha t in rats the dopaminergic agent amphetamine produces a characteristic syndro me ofstereo­ typies and hyperactivity. Amphetamine-induced ste re otypies have been shown to be mediated by th e nigrostriatal system whil e amphetamine-induced hyperac­ tivity is mediated by th e mesolimbic system (11, 12). Typical neu roleptic agents

TABLE 1.

Summary of Animal Models for Tardive Dyskinesia Paradigm T ypical Neuroleptics Atypical Ne uroleptics Behavioral ac ute : ! ampe tam ine induced ! amphet amine induced supe rsensitivity hyperactivity hyperact ivity ! amphet amine induced N.C. amphe ta mine in- ste reotypy duced stereotypy chro nic: i amphet amine induced i amphetamine ind uced stereotyp y stereotypy i ampheta mine induced .C. amphe ta m ine in- ste reotypy duced stereotypy Receptor chro nic: i receptor density - nu- i recepto r den sity - nu- supersensitivity cleus accumbens cleu s accumben s i receptor density - stria- N.C. receptor density tum striatum Depolarization acute: i firing rate - A9 N .C. or ! firing rat e - A9 ina ctivation i firing rate - Al 0 i firing rat e - A l 0 chro nic: ! firing rat e - A9 N. C. firing rat e - A9 ! firing rate - Al 0 ! fir ing rat e - Al 0 Effects of acute and chronic treatments with typical and atypical neuroleptics on amphetamine-induced hyperactivity and stereotypies, on dopamine recepto r den sity in nucleus accumbens and striatum and on the firing rate of neurons in A9 and Al 0 midbrain dopaminergic nuclei . N.C. indicates no change. 6 JEFFERSON JOURN AL O F PSYCHIATRY acutely block both amphetamine-induced stereotypies and hyperactivity sug­ gesting that they induce a net dopaminergic block ade in both th e n igrostriatal and the mesolimbic systems. The prototypical atypi cal ag ent c1ozapine, con­ versely, inhibits only amphetamine-induced hyperactivity whil e paradoxically enhancing amphetamine-induced stereotypies (13-17). Clozapine , th erefore , appears to block dopaminergic transmission only in th e mesolimbic system whi le sparing or possibly enhancing nigrostriatal dopaminergic transmi ssio n. T hio­ ridazine (16-18), sulpiride (13 ,16,17,19-21 ) and molindone (22) also potentiate amphetamine-induced stereotypies suggesting that th ese agents also spare nigrostriatal system functioning. Following chronic treatment with typical neuroleptic agents, rat s show an increased sensitivity for developing amphetamine-induced ste reotypies and hyperactivity. This increased sensitivity is thought to result fr om a co mpensa­ tory supersensitivity of nigrostriatal and mesolimbic dopaminergic receptors following prolonged blockade. In contrast to typical agents, clozapine has been shown to induce supersensitivity only of amp hetamine-ind uced hyperact ivity and not ofamphetamine-induced ste rotypies (14,1 5) suggesting that it does not induce long-term changes in nigrostriatal system functioning.T h ioridazine (23), sulpiride (19) and molindone (24,25) either do not induce supe rsensitivity to amphetamine-induced stereotypies in rats following chronic treatment or do so with considerably less potency than equivalent dosages o f traditional agents. While a relationship between behavioral supersensitivity to am pheta mi ne and TD ha s yet to be demonstrated, th e relative ability of th ese proposed atypical agents to spare the nigrostriatal system suggests that th ese agents may be less likely than typical agents to induce long-term change s in th e nigro striaral system.

Receptor Supersensitivity

In order to investigate whether dopamine receptor superse nsitiv ity under­ lies the neuroleptic-induced behavioral supersensitivity, dopamine recepto rs in the striatum and nucleus accumbens have been stud ied d irectl y using radiola­ belled agents which bind specificall y to D2-type dopamine receptors (e.g. [3H]spiperone). Traditional neuroleptics have been shown to induce an increase in the number of D2 receptors in the striatum following days to weeks of continuous treatment. By contrast clozapine ( 14 ,15,26), sulpiride (26, 27) and molindone (24) do not induce supersensitivity ofstriatal D2 receptors, suggesting again that these agents affect nigrostriatal dopaminergic transmi ssion to a lesser extent than traditional agents do. Shortly after the discovery of neuroleptic-induced supersensitivity of striatal D2 receptors it was proposed that dyskinetic movements result from the interaction of endogenous dopamine with the supersensitive D2 receptors (28,29). Recent findings, however, have called this th eory into question (30). First, receptor supersensitivity can develop after a single ad min istration of MECHANISMS A ND T HERAPEUTIC IMPLICATIONS 7 neuroleptics whereas dyskinetic symptoms arise only after prolonged adminis­ tration. Second, receptor supersensitivit y develops in all subjects tested, while TD devel ops sporadicall y. Third, receptor supersens itivity remains reversible upon withdrawal of neuroleptics while TD may persist indefin itely. Finally, detailed post-mortem studies have fail ed to find an association between striatal

D2 receptor densit y and a prior history of T D (3 1). D2 receptor supersensitivity, th erefore, is probably not mechan isticall y related to TD. Receptor su persensi­ tivity may however be seen as a step in the cascade of events wh ich ultimately results in th e expression of dyskinetic sym pto ms .

Depolarization Inactivation

In add ition to th eir behavioral and bioch emical effects, neuroleptics have been shown to directl y affect th e fir ing patterns of dopaminergic neurons in the A9 and Al 0 midbrain nuclei, whi ch originate in the nigrostriat al and rnesolim­ bic/mesocortical pathways respecti vely. Block ade ofdopaminergic transmission depolarizes neurons in both th e A9 and Al 0 nuclei, leading to an ac ute increase in their firing rate (32). Following chronic neuroleptic-induced depolarization, however, th ese neurons grad ually lose their coord inated pa ttern of firing and over time become com pletely quiescent. Direct ad m in istration of -y-am inobu­ tyri c ac id (GA BA) , an in h ibitory transmi tter, can restore activity to these inact ivated neurons suggesting th at th eir inacti vati on is due to chron ic depolar­ izat ion (33). Neuroleptic-ind uced depolarization of A l 0 neurons is thought to underlie the antipsychotic effec ts of neuroleptics and possibly th eir behavioral side effec ts whil e doplarization inacti vation of A9 neurons may be the first step in a sequence of even ts leading to T D (34). In this theory (35), it is hypothesized that block ade o f postsynaptic striata l dopamine receptors leads to a decrease in the ac tivi ty of th e normall y inhibitory GABA- med iate d striatonigral feedback pathway whi ch lead s to a depolarizati on of A9 neurons and an ac ute increase of striata l dopamine release . Following prolonged dopaminergic blockade , how­ ever, the A9 neurons become incapable of susta in ing the increased firing rate and become grad ua lly inacti ve leading to a decline in striatal dopamine release . As long as th e str iato n igral GABAergic ne urons remain intact, th e process remains reversible . Dopaminergic denervation of th e GABAergic neurons, however, appears to place an adaptive stress upon them wh ich over time may facilitate th eir degeneration. Degenerati o n of GABAergic str iatonigral neurons ha s been implicat ed in th e pathophysiology of Huntington's chorea (10) and Wilso n's disease, co ndi tions wh ich present with dys kinetic symptoms clinically ind isti nguis hable from those of T D, and so may be the fina l co mmon pathway fo r the ge neration of dyskinetic movements. Experimenta l destruc tion of the str iatonigral pathway in animals leads to depolarizat ion inacti vation in A9 and to the development ofdyskinetic movements (36). Cebus monkeys who are exposed to neuroleptics over a period of years can dev elop dyskinesias which closely resem ble those of T D (3 7). Mo nk eys who develop dyskinesias have been shown 8 JEFFERSON JOURNAL OF PSYCHI A TRY to have significantly lower levels of GABA in the substantia nigra th an monkeys who do not (38) suggesting that a failure of GABAergic neurons to adapt to functional dopaminergic denervation may be etiologically relat ed to th e devel­ opment of dyskinesias. Human post-mortem studies o f sch izoph renics have likewise demonstrated a decreased striatal GABA lev el in subjects with a prior history of TD versus those without (31). 0 differences in dopamine recepto r numbers were found in these patients. These findings suggest th at while depolarization inactivation of A9 neurons does not directl y underlie dyski netic movements. It may be the first of a cascade of events whi ch ultimately resul ts in TD. Agents which do not induce depolarization ina ctivation of A9 neurons, therefore, should be relatively without dyskinetogenic potential. Administration of the traditional neuroleptics chlorpromazine, hal oper i­ dol and fluphenazine has been shown to lead to an ac ute increase in th e firi ng rate of neurons in both A9 and A I0 followed by a sustained depolarizati on inactivation of these neurons (39-41). By contrast, clozapine (33,39,40), thi o­ ridazine (39), sulpiride (39) and molindone (39) have been shown not to induce depolarization inactivation in A9. Acute administration ofth ese agents increases the firing rate of neurons in Al 0 but not in A9 while th eir chronic ad m inistra­ tion leads to a decrease in the firing rates of neurons only in Al O. Clozapine an d molindone (41) have also been shown to reverse th e inhibition of firing rates induced by ch ronic haloperidol at the dosages used in th ese stu d ies. Clozapine , thioridazine, sulpiride and molindone therefore , appear not to inhibit nigro­ striatal dopaminergic transmission and so ma y be less likely than tradition al agents to induce TD. l-Sulpiride, the "active" isomer o f sulpiride, has been shown to induce depolarization inactivation of A9 wh en administered o n its own whereas d-sulpiride, the " inactive" isomer, has no effec t (33). Fo r sulpiride, therefore, at ypicality may depend upon administering racemate l-sul piride which is the clinically available form of the d rug.

Possible Mechanisms ofN eu roleptic Atypicality

The exact mechanism by which atypical neuroleptics spare th e nigrostriat al system remains a question of intense debate. One common a bility of all putat ive atypicals is to selectively increase presynaptic dopamine release in th e striatum. Presynaptic dopamine synthesis and release can be assayed either by mea suring the activity of tyrosine hydroxylase, the rate limiting en zyme responsibl e for dopamine synthesis, or by directly measuring the levels of dopamine metabo­ lites. Using these assays, it has been found that c1ozapine, thioridazine, sulpiride and molindone all increase dopamine synthesis and release in the striatum but that they differ in the mechanism by which they do so. Clozapine and thiorida­ zine have been found to stimulate tyrosine hydroxylase activity via non­ haloperidol sensitive receptors (43) and to increase DA metabolite levels via a transsynaptic mechanism (44). Molindone (44) and sulpiride (45 ), co nversely, appear to operate via a homosynaptic mechanism. The at ypical effec ts of MECH ANI SMS AN D T HE RA PEUTIC IMPLICATIONS 9 clozapine and thioridazine, th erefore , are probably mediated via thei r actions on th e non-dopaminergic brain systems whi ch regulate dopaminergic transmission whil e th e at ypical effec ts ofmolindone and sulpir ide are most p robably mediated via their direct effec ts on th e dopaminergic terminals. Clozapine and to a lesser ex te nt thioridazin e have been shown to have relatively low potencies of ac tion at brain O2 receptors and relatively high potencies at D. dopaminergic receptors, at adrenergic receptors, at m uscarinic cholinergic receptors and at serotonergic receptors (46,47). It remains unclear whi ch if any of these rec eptors mediates the atypi cal effec ts of clozapine and thioridazin e . Most attention has been foc used upon anti-cholinergic and anti­ adrenergic effec ts (48, 49). More recently it has been suggested that the anti­ serito ne rgic potency ofclozapine may contribute to its atypica lity as well. In one study, LSD, a seroto ne rgic ag onist, potentiated the hyperact ivity induced by the dopaminergic ag ent apomorphine. Clozapine but not haloperidol or su ipiride inhibited the LSD-induced potentiation of apomorphine hyperacti vity (50) suggesting that clozapine has a distinct effec t on brain serotonergic systems whe n compared with other neuroleptics. Thioridazine was not ex plicitly tested in this paradi gm. Striatum (5 I) and substantia nigra (32) receive in nervation from brain serotonergic systems suggesting that seroto ni n may play a modula­ tory role in nigrostriatal syste m functio ning. The mech an ism by wh ich cloza­ pine's anti-serotonergic effec ts might result in a decreased dyskinetic potenti al, however, remains to be determined. By contrast to clozapine and thioridazine , molindone and sulpiride bind ex tremely weakl y to OJ receptors, to muscarinic cholinergic receptors, to ad renergic receptors and to se rotonergic receptors (46, 47). Both mol indone and sulpiride, however, bind potently to a class of dopamine receptors called dopamine autoreceptors (OARs). OARs respond directl y to pre-synaptically rel eased dopamine and serve to inhibit further dopamine release. Blockade of this negative feedback system effec tively increases th e rate of pre-synaptic dopamine synthesis and release (52 ). Low dose apomorphine «0.4 mg/kg) selec tively stim ulates OARs (53). Usin g apomor ph ine to assess DAR function­ ing, it has been found that molindone inhibits DARs 2-4 ti mes more potently than post-synaptic receptors. In th e dose ra nge of 1- 3 mg/kg, molindone preferentially inhibits OARs (22,54-56). Sulpiride has also been shown to preferentially inhibit OARs, at doses up to 10 mg/kg (2 1,53). Cloza pi ne and thioridazine, as opposed to molindone and sulpiride, appear to antagonize DAR-mediated activities extremely weakly (53, 54) . OARs have been shown to regulate dopamine release in the nigrostriatal system (59). Agents which act preferentially on OARs, therefore, would be expecte d not to inhibit and possibly to enhanc e dopaminergic neurotransmi ssion in the striatum. Such an effect could underlie th e atypical effects of molindone and sulpiride in animal models ofTO. It should be noted, however, that at high doses molindone and sulpir ide can effectively block postsynaptic dopamine rec eptors. At high doses, therefore , these agents might be expected to behave similarly to tradition al neuroleptics. 10 JEFFERSON JOUR N AL OF PSYCHIATRY

A Model f or N egative Symptom s

In addition to regulating nigrostriatal functioning, OAR s regulate meso­ limbic dopaminergic transmission (52 ,60,6 I) . Stimulation of postsynaptic dopa­ mine receptors with amphetamine or high dose apomorphine has been shown to induce motor hyperactivity which is mediated via th e mesolimbic system. Low dose apomorphine, conversely, binds preferentially to OARs, leadi ng to decreased mesolimbic dopamine release and a charac te ristic syndrome of hypomotility and sedation in rodents (53) . Neither clo zapine nor thioridazine reverses the hypomotility induced by low dose apomorphine (53). T hese agents , therefore, appear to have littl e ability to reverse mesolimbic dopaminergic blockade. Conversely su lpiride has been shown to inhibit apomorphine-induced hypom otility (53) suggesting th at it may not induce net dopaminergic underac­ tivity in the mesolimbic system when administered alone. While th e effec t of molindone on hypo motility has not been explicitly tested, mol indone ha s been shown to inh ibit the effects of low dose apomorphine on dopamine re lease (54,56) and so wo uld be expected to share su lpiride's behavioral effec ts. T he relationship between apomorphine-induced hypomotility and schizo­ phrenic symptomatology remains to be determined. In one stu dy (62), however , it was shown that apomorphine-induced hypomotility is accompanied by a reward deficit in rats. Untreated rats show an ability to increase th eir ra te of bar pressing when they are shifted from a sched ule in whi ch th ey are rewarded with a food pellet for each response to one in whi ch they are rewarded for o nly every fourth response. After three sessions untreated rats are able to obtai n the same number of pellets as before th e shift in reward sch edule. Rats pretreated with low dose apomorphine , however, fail to significa nt ly alter their ra te of responding following th e shift in reward sch edule. Sin ce th e rat s remain ph ysicall y capable of increasing their responding rat e, th is failure of responding ma y represent a decreased responsiveness to sec ondary reinforcers. It was proposed that this decreased re sponsiveness might represent a model for depressive-like negative schizophrenic sympto ms such as anhedonia and emo­ tional withdrawal. Sulpiride completely reverses th e reward deficit induced by apomorphine. Thioridazine, haloperidol, chlorpromazin e and fluphenazine by contrast fail to reverse the apornophine-induced reward deficit at any dose. Molindone has not been explicitly tested in this paradigm. In man, the mesolimbic system appears to regulate behavioral ac tivity and mood. Low dose apomorphine produces sedation and sleep and ma y precipitate severe depression (63 ). Underactivity of th e mesolimbic syste m appears to be involved in the psychomotor retardation and poor env ironmental react ivity seen in patients with Parkinson's disease (9) and endoge nous depression (64,65). Furthermore, based upon animal models, it has been po stulated th at OAR­ hypersensitivity, leading to diminished mesolimbic dopam ine release, might be etio logic in some forms of retarded depression (66). T he role of OAR s in humans, th erefore, ma y be similar to th eir role in rodents. T he ability of MECHANISMS AND THERAPEUTIC IMPLICATIONS I I molindone and sulpiride to preferentially block OARs might predict that these agents could preferentially treat th e depressive-like negati ve sym ptoms includ­ ing psychomotor retardation and emotio na l withdrawal.

CLINICAL STUDIES

While the basi c models of T O and negative sym pto ms suggest th at c1ozapine, thioridazine, sulpir ide and molindone ma y produce atypical clinical effects, ultimate confir matio n or refutation of these predict ions ca n o nly be obtained from detailed clinical stud ies. Sin ce TO generall y develops 1- 2 years afte r the initiation of neuroleptic therapy and occu rs only in a mi nority of subjects (66), definitive comparison of the relative dyskinetogenic pote ntial o f neuroleptics requires long-term longitudinal stud ies of first break schizophrenic pati ents spanning several years and in vol vin g large numbers of subjects. O f th e four neuroleptics which show atypical effects in animal models, on ly cloza pine has been subj ecte d to sufficient study to suggest th at it has signi ficantly lower dyskinetogenic potential than traditional agents. In one stu dy of 21 6 psyc hiatric patients treated with clozapine as sole neuroleptic'for up to 12 yea rs no cases of TO were reported (67 ). Other studies have sim ilarly show n a decreased d yski­ netic potential for clozapine (68). Thioridazine , sulpiride an d mol indone , by contrast, ha ve not been subject ed to suffici ently long-t erm stu d ies to allow an estimation of th eir dyskinetic potential ve rs us traditional agents. In th e absence of long-term longitudinal stud ies of schizophrenic patients, "masking" paradigms have been used to try to study th e relat ive dys kinetogenic potentials of neuroleptic agents. In this approach, subjects are chosen who have developed persistent withdrawal exacerbated TO. These subjects are assigned to different neuroleptic regimens and th e potency with which th ese agents mask dyskinetic symptoms is determined. Based upon anima l studies (37,69,70), it ha s been proposed that those agents which are least potent in masking dys kinetic sym pto ms should be least likely to induce de novo TO. In a closely related paradigm, subjects with preexisting TO are exposed to neuroleptics and the post- vs. pre-exposure severity of TO is determined. Studies usin g th ese paradigms have been conducted with haloperidol and with th e proposed atypicals clozapine, thioridazine and molindone . Acti ve treatment with haloperi­ dol has been shown to potently mask dyskinetic symptoms . Subsequent with­ drawal of haloperidol leads to a rebound worsening of dyskineti c symptoms sugge sting th at a progression of the underlying process has occured (69-76). Clozapine, by contrast , has been shown to have no sign ifica nt an tidys kine tic effects and withdrawal ofclozapine does not lead to rebound worsening (70, 7 1). Thioridazine (70 ) and molindone (72) also mask d yskineti c symptoms less potently than haloperidol does. These agents, however, do produce a significant degree of masking and therefore cannot be co nsidered fr ee of dyskinetogenic potential. While sulpiride has been shown in humans to have some ability to mask dyskineti c symptoms (73,74) , its potency has not been directl y co mpared 12 JEFFERSON J O UR NAL OF PSYCHIATRY either to traditional neuroleptics or to other atypicals . In Cebus monkeys with persistent neuroleptic-induced orofac ial d yskinesias sulpiride has been shown to mask dyskinetic movements to a lesser degree th an either ha loperidol or fluphenazin e (75). In addition to c1 ozapine , thioridazine (70) and sul piride (75) do not induce rebound worsening of TO. Addit ionall y, clozapine and thiorida­ zine ha ve also been found not to induce rebound worsening in Cebus monkeys with persistent dyskinesias (76). Molindone has not been d irectly tested in th e rebound worsening paradigm.T hese stud ies support the basic prediction that c1ozapine, thioridazin e, sulpiride an d molindone have relatively decreased dyskinetogenic potential when co mpared with traditional agents. Only c1oza­ pine, however, appears inactive in these paradigms, suggesti ng th at the other three agents might still ha ve sign ificant although decreased risks of associated T O. Furthermore, although thioridazine does not p roduce rebound worsening of TO in monkeys, two of its metabolites, mesoridazin e and sulforidazine, have been shown to induce rebound worsening while a third metabolite, thioridazine ring sulfoxide, does not (69) . Individual metabolism may therefore affect wh ether thioridazine and possibl y other neuroleptics have decreased dyskineto ­ genic potential in an y given subject. Negative symptoms have also proven diffi cult to study clinically. No definitive stud ies ha ve been co nd uc ted wh ich either support or refute the suggestion that sulpiride and molindone should be more efficacious than other neuroleptics in treating negati ve symptoms . Difficulties arise because negative sym ptoms have proven diffi cult both to define and operationa lize. In the last few yea rs, however, phenomenological stud ies ha ve demonstrated that depressive­ like negative symptoms (e.g . fatigue , blunted affect and loss of interest) consti­ tute a cluster of symptoms whi ch are d istinct from either positive or hebephren­ ic-lik e negative sym ptoms (77,78). T he sepa rate cluste ring of th ese symptoms suggests that they may be etiologically di stinct fr om o ther sym ptoms of schizo­ phrenia and may possibl y be mediated by different brain pathways. Operational­ ized criteria for negative symptoms have been proposed on ly within th e last few years (79 ,80). Since no stud ies have di rectl y co mpa red neuroleptics usin g well validated negative symptom scales, no firm conclusions ca n be drawn concerning the relative effectiveness of typi cal and at ypical neuroleptics in treating negative symptoms. Preliminary conclusions can be drawn, however, fr om medication trials which utilized the Brief Psychiatric Rating Scal e (BPRS) (8 I). Three BP RS items, emotional withdrawal, blunted affect, and motor retardation have been found to correlate with negative symptoms scores but not with positiv e symp­ toms suggesting that they might be useful post-hoc measures of negati ve symptomatology (77 ,82) . These symptoms are commonly com bined to form the withdrawal/retardation subseaIe (8 I) . In reviewing three stud ies (83-85) which com pa red clozapine either to ba seline or to reference neuroleptic (chlorpromazine or haloperidol), clozapine significa ntly improved symptoms of withdrawal and retardation in two of the three. In none of these studies, however, were th e differences significant versus MECHANISMS AND T HE RA PEU T IC IMPLICATIONS 13 a reference neuroleptic. In a fourth study, clozapine fa iled to im prove an y of th e BPRS negative sym ptoms (86). Perhaps most indicat ive of th e effects of cloza­ pine are the results of a large multicenter European study (87) in whi ch clozapine was compared with three reference neuroleptics. While clozapine was effec tive overall in treating BPRS negative symptoms, no clear d ifferential effect was observed. In one substudy, clozapine was superior to chlorpromazine in th e treatment of withd rawal/retardation. The differential effect, however, was less th an for h yperacti vit y and co re symptoms, however, suggesting that clozapine's superiority was global rather than restrict ed to negative symptoms . Thioridazine and its acti ve metabolite mesoridazin e have simi larly been compared with reference neuroleptics in a number of stud ies. In three studies (88-90), thioridazine has been sho wn to be relatively ineffecti ve in ameliorating emotio nal withdrawal and psychomotor retardation. Mesoridazin e, its active metabolite, has been shown to be somewhat more effective in the treatment of negative symptoms (89-93) possibl y because it is less seda ting. Mesoridazine also, however, has been found not to be significantly better than reference in treating negative symptoms. Moreover, in one study in whi ch all BPRS symp­ toms improved significantly following treatment with mesoridazine , blunted affect and emotional withdrawal showed th e least improvement (93) . Sulpiride ha s been relatively poorly stud ied in trials wh ich employ the BPRS. In three such studies (94- 96), sulpiride was found to consistently am eliorate emotiona l withdrawal, motor retardation and emotiona l blunting along with the subscal e anergia, although in none of these stud ies was sulpiride sign ifica ntly superior to the reference neuroleptic (ha lope ridol). However , in one study whi ch used the Comprehensive Psych opathological Rating Sca le (C PRS) to compare suipiride vers us cholo rpromazine (97), sulpiride was found to be sign ificantly superio r to chlorp romazine in th e treatm ent of autistic sym ptoms . These symptoms whi ch consisted of inability to fee l, lassitude, withdrawal, reduced speech and slow ness of movement are ana logous to BPRS defined negative sym pto ms but have not been directl y validate d aga inst them. While sulpiride and chlorpromazin e both produced sign ifica nt improvement in global symptomatology and in positive symp toms, sulpiride sig nificantly decreased autistic symptoms whereas chlorpromazine did not. O f interest, sulpiride-induced improvement in negative symptoms was found to be inversely cor related with sulpiride drug concentration such that those subject s with the highest serum sulpiride concentrations were found to have th e lea st improve­ ment in negative symptoms. Moreover, no significant correlation was fo und between serum levels of either sulpiride (or ch lo rpromazine) and positive sch izop hren ic symptoms. Since the dosage ofsulpiride used in the last study (800 mg/day) was significantly less than the dosages in the three stud ies employing th e BPRS (1200-1600 mg/d mean final dosage) th e differences in outcome might be related to the dosage differences. Two other uncontroll ed studies have also suggested that sulpiride may have anti-autistic effec ts at dosages of800 (98) and 600- I 200 (99) mg/day. These stud ies, therefore , suggest th at low dose 14 JEFFERSO JOURNAL O F PSYCHIATRY sulpir ide may have relatively improved efficacy in treating negative symptoms althoug h at high doses th is differential effect may be lost. O f 16 clinical trials with molindone, 7 have compared it to a referen ce neuroleptic using the BPRS (100-106). O f these, six demonstrated improve­ ment either in the items; emotional withdrawal, motor retardation and blunted affect or in the withdrawal/re tardation subscale whic h encompasses these items. O f th e fo ur studies whic h measured the wit hdrawal/retardation subscale explic­ itly (103-106), all four demonstrated a significant response of these symptoms to molindone but no t to refere nce neuroleptic. In th ree of these stu d ies, th e preferential effects of mol indone on negative symptoms were statisticall y signifi­ cant. These studies support the prediction based upon animal models th at mol indone may be superior to traditional neuroleptics in th e treatment of negative symptoms.

T HERA PEUTIC IMPLICAT IONS

T hese clinical studies support the animal model-based predictions th at clozapine, th ioridazine, mol indone , and su lpiride may have relatively decreased dyskinetogenic potential compared with traditional agents. Only clozapine , however, appears completely free of associated TO. Of the four at ypical agents, only two , th ioridazine and molindone, are currently available for non­ ex per imental use in the U .S. T hese agents appear to differ in the me chanism of their atypicality and in th eir clinical effects. T hioridazine which is a relatively sedating ne uroleptic with no apparent specific efficacy in treating negative symptoms appears to be more clozapine-like in its mechanism of atypicality. Molindone, conversely, more closely resembles the proposed at ypical agent sulpiride and appears to prod uce atypical clinical effects by virtue of its ability to se lective ly block presyna ptic dopami ne autoreceptors (OARs). Molindone, like sulpir ide, has been shown to be rela tively more effective in treating negative symptoms of schizophrenia tha n traditional neuroleptics. A theoretical concern with molindone is that, like sulpi ride, it may lose its atypicality at high dosages. In an imal studies, molindone has been shown to lose some degree ofatypicality at dosages over 3 mg/kg (24,25). Whether a similar therapeutic window exists clinically remains to be determined .

REFER ENCES

1. Angrist B, Ro trosen j , Gershon S: Differential effects of amphe tami ne an d neuroleptics on negative vs. positive symptoms in schizophrenia. Psych opharmacol 72:17-19, 1980 2. Andreasen NC : egative syndrome in schizophre nia: Strategi es for long-term management, in Chronic Treatment in Neuropsychiatry. Edited by Kem ali 0 , Racagn i G . New York, Raven Pr ess, 1985 3. Rifki n A, Quitkin F, Kanej, et a l: Are prophy lactic antiparkinson drugs ne cessary? Arch Ge n Psyc hiatry 35 :483-489, 1978 MECHANISMS A ND THERAPEUTIC IMPLICATIONS 15

4. Rifkin A, Quitkin F, Klein DF: Akinesia. Arch Ge n Psych iatry 32:672-674, 197 5 5. Tard ive dyskin esia an d th ioridazine [letter). Arch Gen Psychiatry 41 :414-41 6, 1984 6. On Sandoz's claim of thi oridazine's co mparative safety [letter ]. Am J Psych iat ry 140 :1645-1 64 8,1 983 7. Ca rlsson A: Antipsyc hotic drugs, neurotransmitt ers, and schizophrenia. Am J Psychi atry 135:164-173, 197 8 8. Hornykiewicz 0: Psych opharmacological implicat io ns of dopamine and dopamine antagonists: a critical evalua tion ofcurrent evidence. Ne urosci 3:773- 783, 197 8 9. Price KS, Farley IJ, Hornykiewicz 0: Ne uroche mistry of Parkinson's disease: Relation between striat al and limbic dopam ine. Ad v Bioch em Psychopharmacol 19:293-300, 197 8 10. McGeer PL , McG eer EG:T he GABA system and fu nction of the basal ganglia: Huntington's d isease, in GABA in Nervous Syste m Function . Ed ited by Roberts E, Ch ase TN, Tower DB. New York, Raven Press, 197 6 II . Costa II B, Na ylor RJ, Cannon JG, Lee T: Differentiation of the dopamine mecha ­ nism mediating stereotyped behiour and hyperact ivity in the nucleus accumben s and ca udate putamen. J Ph arm Pharmacol 29: 337 -342, 1977 12. Kelly PH , Seviour PW, Iversen SD: Amphe ta mine and apo morphine responses in th e ra t following 6-0HDA lesions of the nu cleus acc umbens sep tia and corpu s striatum. Brain Res 94:5 07-522, 197 5 13. Robertson A, MacD on ald C: Atypical neuroleptics clozapine and thioridazine enha nce amphet am ine-induced stereotypy. Pharmacol Biochem Beh av 21 :97- 10 1, 1984 14. Seege r TF, T ha i L, Gardner E: Behavioral an d biochemica l aspects of neu rol eptic induced dopa minergic supersensitivity: St udies with chronic clozapine and haloper­ idol. Psych opharmacol 76 :182- 7, 1982 15. Rupniak MJ, Hall MD , Mann S, Fle minger S, Kilpatrick G, Jenner P, Marsden C D: Chronic treatm ent with c1ozapine, unlike haloper idol, does not induce cha nges in striata l D-2 receptor fu nction in th e rat. Bioch emical Pharmacol 34:2755-2763, 1985 16. Ljunberg T , Ungers tedt U : Classification of neuroleptic drugs according to the ir ability to in hibit apo morphine- ind uce d locom otion and gn awing: Evidence for two different mech anisms ofac tion. Psych oph armacol 56:239-247, 1978 17. Cos ta II B, Na ylor RJ: Det ect io n ofth e neuroleptic properties ofciozapine, sulpiride and thioridazine. Psych opharm acoI 4 3:69-74, 1975 18. Lai H , Carino MA, Sperry R, Horita A: Effec ts of thioridazine on apomorphine­ elicite d ste reotypic beh avior and motor ac tivity. Ph armacol Bioch em Beh av 13:397-401 ,1 980 19. Vasse M, Protais P, Coste nt in J , Schwa rtz J-C:Unexpected potentiation by discriminant benzamide derivatives ofstereotyped be hav iours elicited by dopamine agon ists in mice. Na unyn-Schmeidberg's Arch Ph armacol 329: 108- 116, 1985 20. Robert son A, MacD on ald C: Opposite effects of sulpiride and metoclopramide on amphetami ne-induced stereotypy. Eur J Ph armacol 109:81 - 89, 1985 2 I . Robertson A, MacDonald C: The effects of some atypical neu rol eptics on ap om or­ phine-induced behaviors as a measure of th eir relative potenices in blocki ng presyna ptic vers us po stsynaptic dopamine receptors. Ph armacol Biochem Beh av 24: 1639- 1643, 1986 16 J EFFERSO N J O UR NAL OF PSYCHIATRY

22. Conway P,U re tsky NJ: Enha nced ste reotyped response to amphetamine after pretreatment with sma ll doses of molindone. Ne uropharmacol 22:579-586, 1983 23. DeV eaugh-GeissJ, Devan and DP, Ca rey RJ: Different ial liabilities of haloperidol and thioridazine for induc ing apomorphi ne hypersensitivity. Bioi Psychi atry 17:12 89-1 301 ,1982 24. Meller E: Chronic molindone treatme nt : relative inability to elicit dopamine receptor supersensitivity in rat s. Psych opharmacol 76:22 2- 227, 1982 25. Koller W, Curtin J, Fields J: Molindone co mpa re d to hal operidol in a Guinea-Pig model of tardive dyskin esia. europha rmacol 23: 1191 -11 94, 1984 26. J enner P, Rupniak NMJ , Marsden C D: Differential alte ration of str iatal 0-1 an d 0-2 receptors induced by th e long-t erm administra tion of haloperidol, su lpiride, or clozapine to rats. Psychopharmacol Suppl 2: I 74 -1 81 , 1985 27 . BannetJ, Gillis S, Ebst ein RP , Belm aker RH: Effec t of chro nic sulpiride on striata l spipe rone binding. Int Pharmacopsychiat 15:334- 337 , 1980 28 . Klawans H, Rubovits R: Effect of choline rgic and anticho linergic agents in tardive dyskinesia. J Neurol Neurosurg Psychi atry 27 :941-94 9, 1974 29. Tarsy 0, Baldessarini RJ: Ph armacologicall y-induced beh avioral super-sensitivity to apomorphine. Nature 245:262-263, 197 3 30. Gerlach J: Pathophysiological mech ani sms underlying tardive dyskin esia. Psycho­ ph armacol Suppl 2:98-103, 1985 3 1. Cross AJ, Crow TJ, Ferrier IN, et al: Che mical an d structu ra l changes in the brain in pati ents with movem ent disorder. Psych opharmacol Sup pl 2: 104-110, 1985 32. Walt ers JR, Lanthorn TH, Waszczak BL, Baring MD , Knigh t M, Steardo L: Modulation of midbrain dopamine ce ll ac tivity, in Ca tec ho lami nes: Neuropharma­ cology and Central ervo us System-Theoretical aspects. New York, Alan R. Liss, Inc., 1984 33 . Chiodo LA , Bunney BS: Typical and atypical neu rol eptics: Differential effects of chronic admi nistratio n on th e ac tivity of A9 and A l 0 midbrain dopaminergic neurons.J Ne urosci 8:1607-16 10, 1983 34. Freema n AS, Bunney BS: Chronic neuroleptic effec ts on dopamine neu ron activity: A model for predicting th erap eutic efficacy and side effec ts?, in Clin ical Pharmacol ­ ogy in Psychiatry. Edit ed by Dahl SG , Gram LF , Paul SM, Potter WZ . New York, Springer-Verlag, 1987 35 . Fibiger HS , Llo yd KG: Neurobiological substrat es of tardi ve dys kinesia: the GABA hypothesis. Trends Neurol Sci 7:462-464, 1984 36. Doudet 0, Bioulac-Sage P, Arluison M, et al: Neurobi ological cha nges induced by neostriata] kainic acid injection: An electrophysiological an d mo rphological approach to the ph ysiopathology of Huntington's chorea, in T he Basal Ganglia. Edited by McKenzie JS, Kemm RE, Wilcock LN. New York, Plenum Press, pp 405-430,1984 , 37. Domino EF: Induction of tardive dyskin esia in Cebus appella and Macaca speciosa monkeys: A review, in Dyskinesia-R esearch and Treatment (Psycho pharmacology Supplementum 2). Edited by Casey DE, Chase TN,Ch riste nsen AV, GerlachJ. New York, Springer-Verlag, 1985 38. Gunne L-M, Haggstrom J-E, Sjoquist B: Association with persistent ne uroleptic­ induced dyskinesia of regional cha nges in brain GABA synthesis. Na ture 309:347­ 349, 1984 39 . White FJ, Wang RY: Differential effec ts of classical and aty pical antipsychotic drugs on A9 and AI0 dopam ine neurons. Science 221 :10 54-1056,1 983 MECH ANISMS AND T HE RA PEUTIC IMPLICATIONS 17

40. Chiodo LA, Bunney BS: Possibl e mech anisms by whi ch repeated clozapine adminis­ trati on differentially affects the activity of two subpopulations of midbrain dopa­ mine neurons.JNeurosci 5:2539- 2544 , 1985 41. Bunney BS, Roth RH , Agh ajanian GK : Effects of mol indone on central dopaminer­ gic neuronal acti vity and metabolism: Sim ilarity to other neurol eptics. Psychophar­ macol Comm 1:349-358, 197 5 43 . Guidotti A, Gale K, T ofano G, Vargas FM: Tolerance to tyrosine hydroxylase activation in N. Accumbesn and C. Striatum afte r repeat ed injection of " classica l" and "atypical" antischizophrenic drugs. Life Sci 23:50 1-506, 1978 44. Walters JR, Roth RH : Dopaminergic neurons: An in vivo system for measuring drug interactions with presynaptic receptors. Arch Ph arm acol 296:5- 14, 1976 45. Herrera-Marschitz M, Stahle L, Tossman U, Zett erst rorn T , Ungerstedt U: Behavioural and biochemical studies with th e ben zarnide sulp ir ide in rats. Acta Psychiatr Scand 311: 147 - 162, 1984 46. Rich elson E: Neuroleptics and neurotransmitter receptors. Psych iatry Annals 10:21 -40,1980 47. Hyttel J, Larsen J-1, Christen sen AV, Arnt J: Receptor-binding profiles of neuro­ leptics, in Dyskinesia -Research a nd Treatment (Psyc ho pha rmacology Supplemen­ tum 2). Edited by Cas ey DE, Ch ase TN, Christensen AV, Gerlac h J. New York, Springer-Verlag, 1985 50 . Morgenstern R, Fink H, Oelssner W: LSD-potentiat ed apomo rphi ne hypermotility: A model for differentiating anti-psych otic dru gs. Ph armacol Biochem Beh av 18:1 3-17,1983 5 1. Geye r MA, Puerto A, Dawsey WJ , Knapp S, Bullard WP , Mandell AJ: H isto logic a nd e nzyma tic stu d ies of th e mesol imbic an mesostriatal serotonergi c pathways. Brain Res 106:241 -256, 1976 52. Roth RH: CNS dopamine autoreceptors: Distribut ion , pharmacology, and fun c­ tion. Ann NY Acad Sci 430 :27- 89 , 1984 53. DiChiara G , Corsini G U, Mereu GP , T issari A, Gessa GL: Se lf-in h ibitory dopamine receptors: Their rol e in th e bioch emical and behavioral effects of low doses of apomorphine. Adv Bioch em Psychopharmacol 19:275- 291 , 1978 54 . Anden N-E, Alander T , Gabowska-Anden M, et al: T he ph a rm acology of pre- and postsynaptic dopamine receptors: Differential effec ts of dopamine recptor agonists and antagonists, in Catecholamines: Neuropharmacology a nd Ce ntral Nervous System-Theoreti cal Aspects. New York, Alan R Liss, In c., 1984 55. Full e r RW , Snoddy HD: Molindone: Higher doses need ed to block pergolide­ induced elevation ofserum corticosterone than to eleva te dopamine met abol ites in brain. Life Sci 13:2357-2361, 198 3 56. Alander T, Grabowska-Anden M, Anden N-E: Ph ysiological significance of dopa­ mine auto recepto rs as studied following th eir selec tive blockad e by mol indone. J Pharm PharmacoI32:780-782, 1980 57 . Kendler KS, Bracha HS, Davis KL : Dopamine autoreceptor and postsynaptic receptor blocking potency of neuroleptics. EurJ Ph a rm acol 79:217-223, 1982 58. Sumners C, deVries JB, Horn AS: Behavioral and neuroch emical studies on apomo rphine-ind uce hypomotility in mice. Ne uropha rmacol 20: 1203-1208, 1981 59. Gonon FG , Buda MJ: Regulat ion of dopamine release by impulse How and by autoreceptors as stu d ied by in vivo volta m metry in th e ra t striatum. Neurosci 14:765-774,1985 60 . Bannon MJ, ReinhardJF, Bunney EB, Roth RH :Uniq ue respon se to ant ipsychotic 18 JEFFERSON JOURNAL OF PSYCHIATRY

drugs is due to absence of terminal autoreceptors in mesocortical dopamine ne urones. Na ture 296:444-446, 1982 6 1. Bannon M] , Wolf ME, Roth RH: Pharmacology ofdopamine neurons inn ervating the prefront al, cingu late, and piriform cortices. Eur j Pharmacol 91: 119-1 25, 1983 62 . Carnoy P, Sooubrie P, Puech A] , Simon P: Per formance deficit induced by low doses of dopamine agonists in rats: Toward a model for approaching th e neurobi­ ology of negative schizophrenic symtpomatology? Bioi Psychiatry 21 :11-22, 1986 63. Meltzer H Y: Relevance of dopamine autoreceptors for psychi atry: Precl inical and clinical studies. Schiz Bull 6:456-475, 1980 64. Willner P: Dopamine and depression: A revi ew of recent evide nce . I. Empirical Studies. Brain Res Rev 6:2 11-224, 1983 65 . Willner P: Dopamine and depression: A review of recent eviden ce. II. T heore tical approaches. Brain Res Rev 6:225-236, 1983 66. Willner P: Dopamine and depress ion : A review of re cent evidence . Ill. The effects ofantidepressant treatm ents. Brain Res Rev 6:237-246, 198 3 66. Baldessarini RJ: Clinical an d ep ide miologic aspects of tardive dyskin esia . j Clin Psych iatry 46:8-13, 1985 67 . Pov lson U], Noring U, Fog R, Gerlach J: Tolerability and th erapeutic effect of c1ozapine. Acta psychiatr scand 71: 176-185, 1985 68. Claghorn jL, Abuzzahab FS, Wang R, Larson C, Gelenberg A] , Klerman G L, Tuason V, Steinbook R: The current status of c1ozapine. Psychopharmacol Bull 19:138- 140, 1983 69 . Gunne LM, Barany S: A monitoring test for the liability of neuroleptic drugs to induce tardive dyskinesia . Psychopharmacol 63: 195 -198, 1979 70 . Gerlach j , Simmelsgaard H : T ardive dysk inesi a during and following treatm ent with haloperidol, haloperidol, biperiden, thioridazine, and c1ozapine. Psychoph ar­ macoI59:105-112,1978 71 . Gerlach j, Thorsen K, Fog R: Extrapyramidal reactions and amine metab olites in cerebrospinal fluid during haloperidol and clozapine treatment of schizophrenic patients. PsychopharmacoI40:341-350, 1975 72 . Glaz er WH, Hafez HM, Banarroche CL: Molindone and haloperidol in tard ive dyskinesia. Moban symposium proceedings, 198 5 73. Casey DE, Gerlach j and Simmelsgaard H : Sulpiride in tardive dyskin esia. Psych o­ pharmacol 66:73-77, 1979 74 . Quinn N, Marsden CD : A double blind trial ofsulpiride in Huntington's disease and tardive dyskinesia. j Neurol Neurosurg and Psychiat 47:844-847, 1984 75 . Haggstrom j E: Effects of sulpiride on persistent neuroleptic-induced dyskin esia in monkeys. Acta Psych iatr Sca nd [Suppl) 311: 103-108, 1984 76 . Kovacic B, Ruffing D, Stanley M: Effect of neuroleptics and of potential new anti-psychotic agents (Mj 13859- 1 and Mj 13980-1) on a monkey mod el of tardive d yskinesia. j Neural Transmission 65: 39-49, 1986 77. Opler LA , Kay SR, Rosado V, Lindenmayerj-P: Positive and negative syndromes in chronic schizophrenic inpatients. j Nerv Mental Disord 172: 317- 325, 198 4 78 . Meltzer HY : Effect of neuroleptics on the schizophrenic syndrome , in Clinica l Ph armacolog y in Psychiatry. Edited by Dahl SG, Gram LF, Paul SM , Potter WZ. New York, Springer-Verlag, 1987 79. Kay SR, Fiszbein A, Opler LA: The positive and negative synd ro me scale (PANSS) for schizophrenia. Schiz Bull 13:261-275, 1987 MECHANISMS AN D T HE RAPEUTIC IMPLICATIONS 19

80 . Andreassen NC : Negative symptoms in sch izophre nia: Defin ition an d reliability. Arch Gen Psychi atry 39:784- 788, 1982 81. Ov erall JE, Gorham DR: Brief psychi atric rating sca le. Psychological Reports 10:799-812, 1962 82. Opler LA, Kay SR , Fiszbein A: Positive and negative syndromes in schizophrenia: T ypological , dimensional, and ph armacological valida tion, in Positive and egative Symptoms in Psychosis: Description, Research and Future Directions. Edited by Harvey PD, Wa lker E, Hillsdale , NJ , Lawren ce Er lbaum Assoc iates Inc., 1986 83. Shopsin B, Klein H, Aaronsom M, Coli ora M: Clozapine, chlorpro maz ine, and placebo in newl y hospitalized , acutely sch izophrenic pat ients. Arc h Gen Psychiatry 36:657-664, 1979 84. Gerlach J , Koppelhau s P, Hel weg E, et al: Clozapine and haloperidol in a single­ blind cross-over trial: Therapeutic and bioch emical aspects in the treatment of schizophrenia . Acta Psychi atr Scand 50:4 10-424, 1974 85. Gell enberg AJ , Doller JC. Clozapine versus chlorpro mazi ne fo r the treatment of schizophrenia: Preliminary results from a double-blind study. J Clin Psychiatry 40 :238-240, 1979 86. Ch ouina rd G, Annabl e L: Clozapine in th e treatment of newly admitted Schizo­ phren ic pati ents. J Clin Ph armacol 289-297 , 197 6 87 . Fisch er-Cornelissen K, Ferneer J. An exa mple of European multicenter trials: Multispectral an alysis o f c1ozapine. Psych opharmacol Bull 12:34- 39, 1976 88. Clark ML, Huber WK ,Chara lampo us KD, Se rfetinides EA , Trousdale W, Colmore JP. Drug treatment in newl y admitt ed schizophrenic pati ents. Arch Ge n Psychiatry 25 :404-409, 1971 89. Vital-H erne J, Gerbino L, Kay SR , Katz IR, Opler LA: Mesoridazine and thiorida­ zine: Clinical effects and blood levels in refra ctory schizophrenics.JClin Psychiatry 47 :37 5-379,1986 90. Sugerman AA :Comparison of T PS-23 an d thioridzi ne in chronic schizophrenic patients. Curr Ther Re s 7:520- 527, 196 5 91 . Ritter RM, Tatum PA: Two studies ofth e effec ts of mesoridazine.J Clin Pharmacol 12:349-355, 1972 92 . Freeman H : A do uble-blind compa rison of me soridzine and chlorpromazine in ch ro nic schizophre nics. Dis Nerv Sys 34:289-293, 197 3 93. Fr eeman H, Oktem MR , Oktem N: A double-blind co mparison of th e therapeutic efficacy of mesoridazine versus ch lorp romazi ne. Curr T he r Res I I :263- 270, 1969 94. Melk e DH, Gallant DM , RonigerJJ, Kessler C, Kessler IR :Sulpiride: Evaluation of antipsyc hotic activity in schizophre nic patients. Dis Ne rv Sys 569-57 1, 1977 95. Rama Rao VA, Bailey J, Bishop M, Coppen A: A clini cal and ph armacodynamic evaluation ofsulpiride. Psychopharmacol 73:77-80, 1981 96 . Munk-Andersen E, Behnke K, Heltberg J , Hielsen H , Gerlach J: Sulpir ide versus haloperidol , a clinical tri al in sch izophre nia: A preliminary report. Acta Psych iatr Scand Suppl 2:31 - 39, 198 3 97 . Alfredson G, Harnryd C, Wiesel F-A: Effects of sulpiride and ch lorpromazine on autistic and positive psychotic sympto ms in schizophre nic pa tien ts-relation ship to drug concentrations. Psychopharmacol 85:8-1 3, 198 5 98. Elizur A, Davidson S. The evaluatio n of th e anti-autistic activity ofsu lpiride . Curr Ther Res 18:578-584, 197 5 99 . Nishiura M: Clinical-pharmacologi cal stu dies of su lpiride . Curr T he r Res 20 : 164­ 169,1976 20 JEFFERSON JOURNAL O F PSYCHIATRY

100. Ga llan t DM, Bishop MP: Molindone: A controlled evaluation in chronic schizo­ phrenic patients. Curr T her Res 10:441-447, 1968 10 1. Binder RE,Glick I, Rice M: A comparative study of parenteral molindone a nd haloperidol in the acutely psychotic patient. J Clin Psychiatry 42:203-206, 1981 102. Simpson GM , Amin M, EdwardsJG: A double-blind compar ison ofmolindon e and trifluoperazine in the treatment of acute schizophrenia. J Clin Pharmacol 11:227­ 236, 197 1 103. T urek IS, Ota KY, De LaRoch a M, et al: T he use ofmolindone in the treatment of ac ute psychotic states: comparison of two dose schedules. J Clin Ph armacol 10:349-355, 1970 104 . Clark ML, H uber WK, Sakate K, et al: Molindone in ch ronic schizophrenia. Clin Pharmacol T her 11:680- 688, 1970 105 . Freeman H , Frederick AND: Comparison of trifluoperazine and molindon e in chronic schizophrenic pa tie nts. Curr Ther Res 11:670-676, 1969 106. Ramsay RA, Ban T A, Lehman HE, et al: Comparative study of molindone and trifluoperazine. Curr T her Res 12:438-440, 1970