Klinik Psikofarmakoloji Bülteni / Cilt 8: Sayı 3, 1998

Pharmacology of New Antipsychotic : Are they Stabilizers of Schizophrenic Psychism?

Pascals JOLLIET1, Michel I30URIN2

SUMMARY în this article, of new antipsychotic drugs are reviewed and discussed.

Key W ords: Antipsychotic Drugs, atypical neuroleptics. Bull.Clin.Psychopharmacol. 8:3 (113-118), 1998

re either in hospital or intensive community prog­ he utilization of chlorpromazine in early 1950's ram. Thus, the failure of conventional therapies to was the beginning of a new era in the treatment T improve the symptoms of a relatively small group of schizophrenia. In the following thirty years nu­ of patients substantially increases the total burden merous neuroleptics have been launched, most of of the disease. An improvement in treatment that them having the same fundamental mechanism i.e. halved the size of this group would reduce total li­ the blockade of receptors, but some fetime direct costs by 37%> (2). of their clinical properties were sometimes different The development of new drugs in the field of inducing a classification based as well upon chemi­ schizophrenia is orientated towards molecules ha­ cal structures as clinical features. The most impor­ ving few side effects but as well an effect on negati­ tant problem using these drugs was the dose equ­ ve symptoms (3). These new drugs may improve ivalence as compared with chlorpromazine. the quality of life of patients, their insertion into so­ While these drugs have shown their efficacy in ciety and decrease the indirect costs linked to social treating schizophrenia, they induce a wide range of burden. Ideally, the therapeutic strategies have to side-effects. Yet psychiatrists tried to use minimal be compared between themselves to optimize the dosages and/or prescribe correctors even if there was not a strong consensus in that practice. On the clinical results and costs. other hand, classical neuroleptics are more efficient The dopaminergic hypothesis of Carlsson and on positive than on negative symptoms, with 25% Crow, based on the fact that positive symptoms are of patients as responders. Taking care of psychotic linked to a hyperactivity of the dopaminergic patients is an economic burden knowing that the system, and negative symptoms to a hypoactivity of epidemiology of schizophrenia comprise between 1 that system, is now modulated by evidence concer­ to 27c of the populations anywhere wide world. The ning other neurotransmitters. Serotonin induces a global costs were estimated in France around 2.3 negative feed back on dopamine release in some billion USD (1). treatment makes up 5.6% of brain areas. Glutamate inhibits subcortical dopami­ this cost with only 76% for neuroleptics. An analy­ nergic activity (4) and a primitive deficit of glutama­ sis of lifetime resource use suggests that just 10% of te was suggested in schizophrenia. Other neuropep­ patients incur nearly 80%< of the total lifetime direct tides such as cholecystokinin and neurotensin are costs. These are the patients with episodes lasting also proposed as modulators of dopaminergic more than 2.5 years and who require long-term ca­ transmission.

1 Service de Pharmacologic, Faculte de Medecine de Paris XII, b, rue du General Sarrail, 94010 - Creteil 2 Trofessor of Pharmacology, GIS Medicament, Department of Pharmacology, Faculty of Medicine, BP. 5350S, 4403d Nantes, France 113 Pharmacology of New Antipsychotic Drugs: are they Stabilizers... / P.Jolliet, M.Bourin

The dopaminergic neurons with long axons, on block D2 and D3 receptors (7). which neuroleptics act include the following four The D4 is selectively blocked by cloza­ pathways: pine which could explain its better efficacy on ref­ 1) The nigro-striatal pathway implicated in pro­ ractory schizophrenia (8,9). ducing extra pyramidal effects. In the stri­ The wide distribution of D2 receptors is an ubi­ atum, dopaminergic neurons are linked with quity expression particularly in neostriatum and

cholinergicO neurors. The blockade of D? ~ re- hypophysis where its blockade explains motor as ceptors induces a stimulation of the central well as neuroendocrinological side effects of the neurons. conventional neuroleptics. Their blockade at limbic 2) The mesolimbic pathway, with anterior sub- area explains their therapeutic effects on the positi­ cortical projections could be implicated in ve symptoms, hallucinations and delusions. Howe­ the initiation of the mobility as well as stabi­ ver, they block dopaminergic transmission in other lization of mood. The hyperactivity in this brain areas, potentially increasing the negative area could be the main cause of positive symptoms and leading to tardive dyskinesia. symptoms of schizophrenia. 3) The meso-cortica! pathway which projects to Blockers of D2 and D3 receptor subtypes the frontal cortex. It participates in amnesic Various research has focused on development of and cognitive processes. The hypoactivity of D2 receptor selective blockers with preferential acti­ this pathway could be responsible for the ne­ ons at mesolimbic level compared to nigro-striatum gative svmptoms. system. The D3 receptor subtype is located in limbic 4) The tubero-infundibular pathway, on which areas but not in the hypophysis or the striatum. dopamine inhibits prolactin secretion of the Benzamide compounds are able to selectively anterior hypophysis by stimulating D2 recep­ block enough D2 and D3 receptors (10). For examp­ tors. le, sulpiride, preferentially blocks at low dosages The blockade of D2 receptors by conventional presynaptic D3 receptors, giving it a bipolar activity. neuroleptics induces amenorrhea-galactorrhea Clinical trials have shown that sulpiride is an effici­ syndrome and decreases libido. ent antipsychotic, yet its side effect profile, particu­ The present hypothesis of schizophrenia is ba­ larly the extra-pyramidal symptoms and hyperpro­ sed on a dopaminergic transmission deficit in nigro- lactinemia, are not correlated with predictions ba­ striatal and mesocortical pathways, contrasting sed on dopaminergic selectivity at D2 receptors (11). with an excess of dopaminergic transmission in me­ A possible explanation is that sulpiride is an solimbic area (5). hydrophilic drug so it does not easily cross the blo­ The development strategies in this field are not od brain barrier. So, it is necessary to use high doses only focused on discovery of specific antagonists of like 600 to 800 mg per day, and even up to 1 g which one subtype of dopaminergic receptor (i.e. D3 etc.) induce side effects. but on synthesis of molecules having different ef­ Remoxipride is a weak D2 blocker, but specific fects regarding the concerned brain areas. for the extrastriatal receptors. On the contrary of typical neuroleptics like haloperidol, animal studies Antipsychotic drugs with selective blockade in rats showed that there were wide differences bet­ of dopaminergic receptors ween the doses of remoxipride in decreasing the lo­ Up to a few years ago, two dopaminergic recep­ comotor activity induced by dopaminergic tor subtypes, D] receptors activating adenylate and those inducing catalepsia. In vivo binding stu­ cyclase and D2 receptors inhibiting adenylate cycla­ dies with D2 receptors have shown, that remoxipri­ se, were known. Stimulation Dj receptors leads to de inhibits the binding of trotted spiperidone in so­ an increase in cAMP production whereas, D2 recep­ me limbic areas more than in the striatum, compa­ tor stimulation inhibits cAMP production. Now, red to typical neuroleptics, which affect identically there are 5 dopaminergic subtypes: D[ and D5 lin­ these two brain areas. Clinical extrapolation from its ked to a Gs protein; D2 and D4 linked to a Gi prote­ psychopharmacological profile seems to indicate in; and the D3 receptor, a presynaptic receptor pla­ that remoxiprid? can induce less extrapyramidal ef­ ying a role on negative feed back (6). The dopami­ fects as well as lower prolactin secretion than classi­ nergic receptor family is wide and there are nume­ cal neuroleptics. Recently, it was shown that remo- rous studies aimed at discovering selective blockers xipride blocks D2 as well as D3 receptors as well as and agonists of each subtype of receptor and to cor­ the sigma receptor. Remoxipiride has been relate the selective binding to a special clinical pro­ shown to antagonize amphetamine induced hyper­ file. locomotor activity and demonstrate fewer stereoty­ Classical neuroleptics such as haloperidol block pic behaviors. The significance of these two effects mainh' D2 receptors, whereas benzamides mainly is not yet very clear. 114 Klinik Psikofarmakoloji Bülteni / Cilt 8: Sayı 3, 1998

Nine multicentre controlled double blind studi­ link between D4 receptor density and treatment res­ es compared remoxipride efficacy with haloperidol ponse, and that it is not a predisposing factor of the in treating acute schizophrenia. In a Canadian study illness (14). (12) 242 schizophrenic patients and 242 patients pre­ senting acute schizophrenia were treated with three Antipsychotic drugs with selective dosages of remoxipride compared to placebo. In a serotoninergic antagonism range of 20 to 600 mg/day, remoxipride was com­ Interest in the serotoninergic system is incre­ parable in efficacy with haloperidol used in a dose asing in recent years because there is evidence that ranging from 15 to 45 mg/day. Remoxipride treated it plays a role in depression, anxiety and more re­ patients had better improvement of their negative cently in schizophrenia (15). symptoms as well as presenting with less extrapyra- midal and neuroendocrinological side effects com­ 5-HT2 receptor blockers pared with haloperidol treated patients. On the ot­ It is known that thioridazine, clozapine and so­ her hand, more patients exhibited akathisia in the me other neuroleptics act as 5-HT2 antagonists besi­ remoxipride group. Tardive dyskinesia risk seems de their activities on the dopaminergic system. Re­ to be less likely to develop with remoxipride com­ cently 5-HT2 selective antagonists have been deve­ pared to haloperidol. Eight cases of aplastic anemia loped. Ritanserin is the most representative of these out of 45000 remoxipride treated patients resulted compounds. This drug wras widely studied. It incre­ in the withdrawal of remoxipride from the Swiss ases the activity of the dopaminergic neurons loca­ market which lead to withdraw.. ted in the mid-brain. This stimulating effect leads to the idea that 5-HT2 receptor blockers could impro­ Agonists of D2 presynaptic receptors ve negative symptoms in schizophrenia. However, These molecules, B-HT 920, EMD 49980, SND there are few clinical trials of the antipsychotic acti­ 919 and roxindole seem to decrease prolactinemia vity of this compound. without inducing catalepsia. The actual evidence is poor and not conclusive (7). 5-HT3 blockers Animal studies lead to evidence that 5-HT3 an­ D2 post-synaptic partial agonists tagonists can reduce hyperactivity induced by do­ D2 partial agonists such as terguride and SDZ paminergic agonists when directly injected in lim­ 208-911 could be effective agents in hypo and hyper bic structures. It was proven in open clinical trials dopaminergic activities. If evidence is found, these that ondansetron which is a 5-HT3 selective blocker, drugs could ameliorate positive and negative had some antipsychotic properties at low but not at symptoms with few extrapyramidal side effects. high doses. Several short term double blind studies confirmed some antipsychotic properties of the D} blockers drug. Yet, the development of ondansetron in schi­ Interest in the D] receptor was raised when evi­ zophrenia was kept aside in favor of other 5-HT3 dence accumulated about the interaction between blockers such granisetron, GR 68 756 C and BRL 46- D, and D2 receptors (13). Derivatives of thioxanthe- 470. Clinical studies of these compounds are pro­ ne i.e. flupenthixol and zuclopenthixol as well as moted and evidence is waited upon to know if the­ clozapine have higher affinity for D] receptor than se kind of drugs have any efficacy in treatment of do phenothiazines. Research in this field was drop­ schizophrenia. ped because there were no selective D] blockers available. Recently, several D1 blockers were deve­ loped i.e. SCH 23390 NO 756, SCH 39166 and A Antipsychotics with simultaneous blockade 69024. However studies with SCH 23390 were stop­ of D2 and 5-HT2 receptors : ped because of toxicity. The other compounds are neurons projecting from the raphe still studied in clinical trial. nuclei, have an inhibitory effect upon dopaminergic

transmission inside the nigro-striatalC> and mesocor- D4 antagonists tical areas leading to decreases in dopamine synthe­ Distribution of mRNA that code for synthesis of sis and release. In schizophrenic patients, this dopa­

D4 receptors shows that it is mainly located in the mine inhibition would be exasperated,“ u ' and mav ^ limbic and mesocortical areas. Blockade of this re­ partly explain the nigro-striatal and mesocortical ceptor could explain the better activity of clozapine dopaminergic hypoactivity (4). This inhibition can and olanzapine in refractory schizophrenia. Post be decreased by serotoninergic antagonists. So the Mortem studies have shown that there was a high most important fact explaining the superiority of density of this receptor in schizophrenic patients. new antipsychotics compared to conventional ne­ However, it has been found that recently, there is no uroleptics is their 5-HT2 antagonism. The antago­

115 Pharmacology of New Antipsychotic Drugs: are they Stabilizers... / P.Jolliet, M.Bourin

nism of 5-HT action at the nigro-striatal and the de effects observed with risperidone were sedation, frontal areas leads to an improvement of negative dry mouth and orthostatic hypotension (19). symptoms and a decrease of extrapyramidal symptoms with better tolerance. Some classical ne­ ANTIPSYCHOTICS WITH ANTAGONISM uroleptics such as thioxanthene derivatives exhibit OF NUMEROUS RECEPTORS, THE a weak 5-HT2 antagonism but very low compared SO CALLED MIXED ANTIPSYCHOTICS to risperidone or clozapine. Considering this latest Active neuroleptics on refractory schizophrenia compound, its 5-HT2 blocking effect is more impor­ have antagonizing activity of numerous receptors: tant than its D2 receptor antagonism. Some authors dopaminergic, alpha-, muscarinic and suggestedo o that there was a ogood correlation betwe- (HI). The ratio 5-HT2/D 2 is greater en 5-HT2/D 2 binding ratio and efficacy upon nega­ than 1 and dopaminergic binding is more important tive symptoms. at limbic and mesocortical Dj and D4 receptor le­ Developments of ziprasidone and sertrindole vels. The first drug showing this profile was cloza­ are now in phase III, those of other drugs like zote- pine but now olanzapine has a similar one. pine, melperone and R-79 598 are at an earlier stage. Clozapine was developed in the beginning of Risperidone is a benzisoxazole derivative with 5- the sixties as a derivative of the dibenzodiazepine HT2 antagonist properties as well as D2 antagonism. family. It wras shown that clozapine had antipsycho­ Several double blind controlled studies using halo- tic properties equal or higher than neuroleptics peridol (20 mg/day) and placebo in chronic schi­ used at that period but with few extra-pyramidal zophrenics (16,17,18) showed that risperidone is a symptoms and no hyperprolactinemia (20). Cloza­ potent antipsychotic drug with an optimal efficacy pine does not induce tardive dyskinesia and could in a range of 4 to 8 mg/day upon negative be active on tardive dyskinesia induced by classical symptoms. Meta-analysis showed a better activity of neuroleptics. At the beginning of 1970's, clinical tri­ risperidone upon negative symptoms comparative als with clozapine w7ere stopped in North America with haloperidol. Furthermore, risperidone induced because it induced agranulocytosis. Clinical interest few extrapyramidal effects. Some patients showed of clozapine was recovered because of its proved ef­ such effects as well as an increase of prolactin. Clini­ ficacy on refractory schizophrenia (around 30% of cal trials comparing risperidone with clozapine, this kind of patients were improved). Recently, clo­ perphenezine and zuclopenthixol have not shown zapine was registered in Europe than in North significant differences in their respective efficacy. America with restrictive conditions because of its On the other hand, efficacy of risperidone on refrac­ hematological toxicity and particularly agranulocy­ tory schizophrenia has not yet been demonstrated. tosis found in at least 0.8% of treated patients. So the only use now is in the treatment of refractory schi­ Alpha-adreno receptor blockers zophrenia with a strict monitoring of the hematolo­ Risperidone is also shown to exert blocking ef­ gical parameters. Beside its efficacy in refractory fects on alpha 1 and alpha 2-adreno receptors. The schizophrenia, clozapine is interesting concerning noradrenergic hypothesis in antipsychotic effect its pharmacological profile which seems to be wi­ emerged ten years ago as a research pathway, but it der than that of classical neuroleptics. It is claimed was not possible to demonstrate that hypernoradre- to have an efficacy on cognitive defect, improve­ nergic activity increased in schizophrenic patients ment of attention verbal fluency and recall memory to exclude it. Numerous neuroleptics possess alpha of schizophrenics. On the other hand, it improves 1 adreno-receptor blocking effects. This property le­ cognitive disorder in Parkinson disease. The major ads to a sedative effect, orthostatic hypotension, side effects of clozapine are hypersialorrhea (33% of tachycardia and vertigo and could potentiate an an­ patients), weight gain as well as convulsions which tihypertensive treatment. It is not known what are are dose-dependent (1 to 4,4% ) (21). the clinical consequences of risperidone alpha 2 ad- Olanzapine is a new antipsychotic drug with a reno-receptors blockade. close psychopharmacological profile with clozapi­ Seroquel exhibits an alpha 1 adreno-receptor ne. Its efficacy wras shown to be better than halope­ blockade higher than its blockade of D2 and 5-HT2 ridol as well as on positive and negative symptoms. receptors. The only study yet published is a compa­ Clinical trials have shown that olanzapine had bet­ rative study with chlorpromazine (385 mg/day). In ter eificacy than haloperidol and risperidone on that study using BPRS, CGI and PANSS, seroquel depressive symptoms and suicidal ideas. It induces (400 mg/day) has not shown any superiority com­ a better improvement of quality of life, already sig­ pared with chlorpromazine. In that clinical, trial nificant after some months of treatment. A potential extrapyramidal effects were not different in the anxiolytic effect of olanzapine is discussed because three groups i.e. seroquel, chlorpromazine and pla­ of the weak consumption of benzodiazepines, less cebo, leading to the idea of some bias. The main si­ drop out linked to anxiety in the olanzapine group 116 Klinik Psikofarmakoloji Bülteni / Cilt 8: Sayı 3, 1998

(22). Tolerance is good with few extra-pyramidal ef­ ticles (for review see 25) and still is under research. fects, no agranulocytosis and no tardive dyskinesia CCK-B receptors are linked with mesolimbic (23). It is too early to say if olanzapine could have an and nigrostriatal dopaminergic pathways, they mo­ efficacy in patients refractory to clozapine treatment dulate dopaminergic function (26). It was shown and if it could treat tardive dyskinesia. that acute and chronic administration of a selective CCK-B receptor blocker (LY 262691) decreases Histaminergic Hj-receptor blockers midbrain dopaminergic cells activity (27). The re­ Clozapine and olanzapine block central histami­ sults are in favor that CCK-B antagonists could ha­ nergic receptors inducing sedative effects as well as ve an antipsychotic effect by modulating dopami­ an orexigenic effect with an increase in weight (24). nergic release. The effect seems to be more physiolo­ gical than blockade of dopaminergic receptors (28). Cholinergic receptor blockers This regulation could avoid the long term side ef­ Cholinergic receptors are implicated in motor fects of neuroleptics such as tardive dyskinesia. activity as well as in amnesic processes. It is not known at the moment if there is any relationship CONCLUSION between clozapine and olanzapine blockade of cho­ The research on antipsychotic drugs with more linergic receptors and their superiority of action on efficacy and tolerance was an important subject du­ negative symptoms. Long term treatment by neuro­ ring the last years (29). Numerous drugs were stu­ leptics induced an hypersensitivity of dopaminergic died. Some of them could be new treatment strate­ receptors and down-regulation of the cholinergic. gies compared with the classical dopaminergic an­ Their implication in tardive dyskinesia is not clear tagonism. The limbic and frontal cortex specificity as well as the effect to prevent them. leads to a better tolerance as well as a better efficacy On the other hand, blockade of cholinergic recep­ on negative symptoms with better quality of life for tors decreased the extrapyramidal side effects but patients and at the end a decrease of the burden of induced parasympatholytic side effects. schizophrenia. It was shown that new antipsychotic drugs decreased by 10% rehospitalisation of respon­ AMINOACID RECEPTOR BLOCKERS ders or non-responders (22). The profile of the new Developments in this field are based on the fact drugs leads to a better dopaminergic balance and that phencyclidine which is N-methyl-D-aspartate decreases in spontaneous instability, and negative (NMDA) receptor blocker, induced psychotic featu­ symptoms as wrell as limiting fluctuations between res in healthy volunteers. Furthermore, glutamate is positive and negative symptoms. 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