RECEPTORS: RELEVANCE TO ANTIPSYCHOTIC DRUGS

Transcription

1 Indian Journal of Pharmacology 2000; 32: EDUCATIONAL FORUM AND 5HT 2 RECEPTORS: RELEVANCE TO ANTIPSYCHOTIC DRUGS Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh Manuscript Received: Revised: Accepted: SUMMARY The dopamine antagonism of antipsychotic drugs and their ability to upregulate striatal sites are the corner-stones of the dopaminergic hypothesis of schizophrenia. The question of the role of in schizophrenia, however, has been reopened by the development of clozapine, which, while being the best known antipsychotic medication has low affinity for most subtypes of class. To explain this atypical action of clozapine, involvement of many other subtypes namely 5-HT 2,, D 5 and D 4 has been postulated. However, most studies hitherto, have not been able to demonstrate any direct involvement of these other subtypes in the action of atypical antipsychotics. The most popular theory to explain the atypical nature of the newer antipsychotics is, their selectivity for the dopamine in limbic area, as compared to the nigrostriatal area of the CNS. Thus, measurements still provide the best predictor of antipsychotic response, extrapyramidal side effects and elevation of prolactin levels. KEY WORDS, 5-HT 2, atypical antipsychotics Introduction Modern pharmacological treatment for schizophrenia began in 1950s with the identification of chlorpromazine's specific antipsychotic action. The hypothesis that the mechanism of antipsychotic action in schizophrenia is mediated by dopamine blockade, has been consistently supported by subsequent research 1,2. Every known antipsychotic blocks dopamine 3. While this does not prove a causal relationship between blockade and antipsychotic response, the association between the two is undeniable 3. The serotonergic hypothesis of schizophrenia preceded the better-known dopaminergic hypothesis. Following Gaddum s demonstration in 1953 that LSD, a hallucinogenic drug, had affinity for serotonin, several lines of evidence suggested a role for serotonin in the pathophysiology of schizophrenia 4-6. However, the development of effective antipsychotic drugs that were antagonists at dopamine led to a greater focus on and investigation of the dopamine system 7. With the success of clozapine, an atypical antipsychotic, interest in the role of serotonin in schizophrenia has been renewed. The serotonergic hypothesis is best viewed as complementary to the dopaminergic hypothesis, rather than an alternative to it, since these systems are anatomically connected and functionally interactive 8,9. Several authors have proposed that the atypical antipsychotics derive their unique efficacy at least partly from their dual serotonin and dopamine antagonism, exploiting the neurochemical interaction between these two systems 8,10. Atypical antipsychotic agents confer many advantages like: a lack of extrapyramidal side effects, better treatment of negative symptoms of schizophrenia and treatment of resistant cases. Therefore, differentiation of the mechanism of action of atypical antipsychotics from that of classical neuroleptics may provide guidelines for the development of new antipsychotic drugs and for clarification of the pathophysiology of schizophrenia. Regulation of by antipsychotic drugs Farde and colleagues 11 proposed that one needs a Correspondence: P. Pandhi

2 , 5HT 2 RECEPTORS AND ANTIPSYCHOTICS 188 threshold of to induce antipsychotic response. Prospective studies have largely confirmed this notion, although it is unclear whether this threshold is 60% or 70% and whether the threshold for inducing response is the same as for maintaining it 12,13. Nonetheless, there is a mechanism of antipsychotic response that relies on alone 14. Further more, it has been noted that as increases, especially as it rises above 80%, the incidence of extrapyramidal side effects increases 11. Elevation of prolactin levels may also show a threshold relationship with respect to 15,16. While may be necessary for response, it is not always sufficient, as there are patients who do not respond despite adequate 17. However, it would be fair to claim that provides a reliable (and perhaps the best) pharmacological predictor of response to antipsychotic medication, extrapyramidal side effects, and elevation of prolactin levels. There are now several antipsychotics that have a lower propensity than typical antipsychotics to cause extrapyramidal side effects and prolactin elevation: clozapine, risperidone, olanzapine, sertindole and quetiapine 9,10,18,19. Given the relevance of for response to antipsychotics, extrapyramidal side effects and prolactin elevation, it is of obvious interest how these antipsychotics compare on this index. Various groups have reported that 6mg/day of risperidone led to 75% to 80%, 10 mg/ day of olanzapine showed an of 66% to 75% while clozapine in therapeutic doses showed an of 30-60% 3,20,21,22. The threshold for antipsychotic response lies in the range of 65%- 70% 14,23. It is interesting, then, that both risperidone and olanzapine become effective antipsychotics only at doses which cross these levels of. Doses of risperidone and olanzapine that do not reach these levels (i.e. <2 mg/day of risperidone and <10mg/day of olanzapine) are not reliably antipsychotic in most clinical situations 3. Clozapine, on the other hand, is able to obtain, an antipsychotic response with levels of (usually 30-60%) that would be insufficient to cause antipsychotic response by themselves 14. Thus, clozapine does not call on the typical mechanism for inducing antipsychotic response; risperidone and olanzapine do. This raises the possibility that despite some similarities in their profile in vitro, the fundamental mechanism of response of clozapine may be different from that of olanzapine and risperidone in patients. While this question can ultimately be resolved in a clinical arena in crossover studies, the data on provides a rationale for why patients who do not respond to risperidone/olanzapine may respond to clozapine and the other way round. Mechanism of lack of extra-pyramidal side effects The most popular hypothesis to explain the lack of extrapyramidal side effects by atypical antipsychotics, is the selective brain action of these agents 19. It is believed that atypical agents (clozapine, sertindole etc.,) demonstrate not only antagonism but also a selective ability to act on cortical dopamine neurons in comparison to nigrostriatal neurons 24. This idea stems from the fact that atypical agents like clozapine and olanzapine uniquely up-regulate dopamine mrnas in the prefrontal and temporal regions of the cerebral cortex but not in the nigrostriatal pathways 24. Typical neuroleptic agents uniformly upregulate dopamine mrna in both the regions 24. These findings lead to the hypothesis that interaction with cortical may be a common site of therapeutic activity of drugs effective in the treatment of schizophrenia 25. This is further supported by the fact that treatment with antagonist but non neuroleptic tiapride 26, produces much less impact on the dopamine mrna s in the cerebral cortex than in the striatum 24. An alternative hypothesis to explain the lack of extrapyramidal side effects of atypical agents was put forward by Deutch et al 27, according to which, interaction with distinct isoforms of the may differentiate atypical from typical antipsychotic drugs. Further research however clearly demonstrate that chronic treatment with all the antipsychotic agents including clozapine, produce similar regulatory effects on both -long isoform -short isoform dopamine 24. Regulation of the D 4 dopamine by antipsychotic drugs Particular attention has recently been paid to the D 4 subtype of the class as a possible candidate for the major dopaminergic site affected in schizophrenia 28,29. This assumption is, in part, based

3 189 on the observation that clozapine has a high affinity for this 28,29. Although treatments with several typical and atypical antipsychotic agents up-regulated D 4 mrnas in both the cerebral cortex and the striatum, treatments with other typical and atypical drugs had no significant effect on the D 4 in either cortical and striatal tissue 30,31. Further more, the non neuroleptic tiapride produces a statistically significant up-regulation of cortical and striatal D 4 mrna 24. These observations thus indicate that the interaction with D 4 neither confers the atypical profile nor is necessarily relevant for the antipsychotic effectiveness of the drugs. A critical role for D 4 in normal brain activity has also been challenged by the observation that 1 in 500 Germans and 4 in 100 Afro-caribbeans who completely lack functional D 4 due to gene mutation 32,33 appear to have no detectable psychiatric abnormalities. These various findings suggest that ligands directed exclusively at D 4 sites may not be particularly effective as antipsychotic agents. A recently conducted placebo controlled study to see the effect of D 4 /5HT 2A antagonist fananserin does not support the role of D 4 in schizophrenia 44. The possibililty could not be excluded, however, that action at the D 4 that are embedded in the same integrated cortical circuits as the subtype could achieve comparable clinical results by acting through adjuvant mechanisms. interaction Contrary to their effect on, typical and atypical antipsychotic agents have down-regulatory effect on the and D 5 subtypes of dopamine 24. In addition, a recent positron emission tomography imaging study has shown that the in the prefrontal cortex is down-regulated in never-medicated schizophrenic patients compared with control (normal) subjects and further is correlated with poor performance on the Wisconsin Card Sort Test of prefrontal function 34. In light of these several findings, it appears that the therapeutic effects of antipsychotics may be related to the upregulation of in the cortex, whereas, the obligatory -downregulation produced by prolonged treatment with the same drugs may be hindering in alleviation of negative and cognitive symptomatology because they may exacerbate an endogenous insufficiency. Regulation of 5HT 2 by antipsychotic agents It has been suggested that drugs may demonstrate atypical clinical features (i.e. less extrapyramidal side effects and prolactin elevation) if they have at least a 10 times higher affinity for serotonin 5HT 2 than in vitro 35,36. In patients this translates into a preferential of 5HT 2 as opposed to 37. Risperidone has better efficacy than conventional antipsychotics against the negative symptoms and cognitive deficits of schizophrenia; these effects have been attributed to high 5HT 2A 12. Clozapine, risperidone and olanzapine all show a higher affinity for 5HT 2 than in vitro but the amount by which 5HT 2 exceeds is unclear. In animal tissues or cloned human, clozapine shows a much higher 5HT 2 / ratio (20 times higher affinity for 5-HT 2 than for ) compared to either risperidone (11 times) or olanzapine (12 times) 38. On the other hand, measurements in rats following subcutaneous injection showed that risperidone had the highest 5HT 2 / affinity ratio (19 times) as compared with clozapine (5.1 times) and olanzapine (7.5 times) 38. Dose of a drug is a central determinant of its, and any systemic comparison across drugs must compare not just the but also the dose- relationships over the clinically relevant dose range 39. Comparing the doses at which clozapine, risperidone and olanzapine saturate the 5HT 2, it was shown by Kapur et al 3., that all the three drugs saturate the 5HT 2 at subtherapeutic doses, suggesting that 5HT 2 alone is an unlikely explanation for their antipsychotic effects. Moreover, the fact that one continues to see an increasing response to clozapine in doses upto mg/day 40, even after saturating the 5HT 2, makes it unlikely that 5HT 2 is the primary source of the antipsychotic effect of clozapine. A similar conclusion was reached by Trichard et al 41 in the study of chlorpromazine and clozapine. It does not rule out the possibility however, that high levels of 5HT 2 blockade may modulate or enhance the ability of blockade to induce or to delay the related side effects 36,37. However, any benefit provided by a mixed 5-HT 2 / model must express itself in a narrow range. Patients

4 , 5HT 2 RECEPTORS AND ANTIPSYCHOTICS 190 taking risperidone and olanzapine, who have high occupancies, experience extrapyramidal side effects and prolactin elevation despite a concomitantly high 5-HT 2 42,43. Conclusion The dopamine antagonism of antipsychotic drugs and their ability to upregulate striatal sites are the cornerstones of the dopaminergic hypothesis of schizophrenia 1,2. It is widely accepted that provides a reliable pharmacological predictor of response to antipsychotic medication, extrapyramidal side effects and elevation of prolactin levels. Lack of extrapyramidal side effects by atypical antipsychotic agents is believed to be due to selective brain action. It has been demonstrated that in contrast to typical agents, these drugs act selectively on the limbic dopaminergic neurons and not on nigrostriatal neurons 19,24. Other implicated in the response to antipsychotic drugs include the 5HT 2, and D 4. Most recent observations, however, have failed to show any direct role for these in the pharmacological response 24,31,32,40,41. They probably have a modulatory and an indirect role, if any. REFERENCES 1. Snyder SH. The dopamine hypothesis of schizophrenia: Focus on dopamine. Am J Psych 1976;133: Meltzer HY, Stahi SM. The dopamine hypothesis of schizophrenia : A review. Schizophr Bull 1976;2: Kapur S, Zipursky RB, Remington G. Clinical and theoretical implications of 5-5HT 2 of clozapine, risperidone and olanzapine in schizophrenia. Am J Psych 1999;156: Breier A. Serotonin, schizophrenia and antipsychotic drug action. Schizophr Res 1995;14: Iqbal N, Van Praag HM. The role of serotonin in schizophrenia. Eur Neuropsychopharmacol 1995;5: Lewis R, Kapur S, Jones C, Dasilva J, Gregory MB, et al. Serotonin 5HT 2 in schizophrenia. A PET study using [ 18 F] setoperone in neuroleptic-naïve patients and normal subjects. Am J Psych 1999;156: Seeman P, Lee T, Chau-Wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine. Nature 976;261: Kapur S, Remington G. Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psych 1996; 153: Ohuoha DC, Hyde TM, Kleinman JE. The role of serotonin in schizophrenia : an overview of the nomenclature, distribution and alterations of serotonin in the central nervous system. Psychopharmacol 1993;112:S5-S Meltzer HY. The role of serotonin in schizophrenia and the place of serotonin-dopamine antagonist antipsychotics. J Clin Psychopharmacol 1995;15:2S-3S. 11. Farde L. Nordstrom AL, Wiesel FA, Pauli S, Halidin C, Sedvall G. Positron emission tomographic analysis of central dopamine in patients treated with classical neuroleptics and clozapine:relation to extrapyramidal side effects. Arch Gen Psych 1992;49: Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psych 1984;151: Tollefson GD, Beasky CM, Tran PV, Street JS, Krueger JA, et al. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psych 1997;154: Nordstrom AL, Farde L, Wiesel FA, Forslund K, Pauli S, Halldin C et al. Central -dopamine in relation to antipsychotic drug effects-a double-blind PET study of schizophrenic patients. Biol Psych 1993;33: Baron JC, Martinot JL, Cambon H, Boulenger JP, Poirier MF, et al. Striatal dopamine during and following withdrawal from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels. Psychopharmacol 1989;99: Schlegel S, Schlosser R, Hiemke C, Nickel O, Bockisch A, Hahn K. Prolactin plasma levels -dopamine measured with IBZM-SPECT. Psychopharmacol 1996;124: Wolkin A, Barouche F, Wolf AP, Rotrosen J, Fowler JS, et al. Dopamine blockade and clinical response: evidence for two biological subgroups of schizophrenia. Am J Psych 1989;146: Kane JM, Freeman HL. Towards more effective antipsychotic treatment. Br J Psych 1994;165: Zimbroff DL, Kane JM, Tamminga CA, Daniel DG, Mack RJ, et al. Sertindole study group: Controlled, dose-response study of sertindole and haloperidol in the treatment of schizophrenia. Am J Psych 1997;154: Nordstrom AL, Farde L, Nyberg S, Karlsson P, Halldin C, Sedvall G., and 5-HT 2 in

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