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Mechanisms of Typical and Atypical Antipsychotic Drug Action in Relation

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Mechanisms of Typical and Atypical Antipsychotic Drug Action in Relation Molecular Psychiatry (1999) 4, 418–428 1999 Stockton Press All rights reserved 1359–4184/99 $15.00 MECHANISMS OF DRUG ACTION Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia GE Duncan1, S Zorn2 and JA Lieberman1 1Department of Psychiatry and UNC Neuroscience Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599; 2NS Discovery, Pfizer Inc, Central Research Division, Pfizer Inc, Groton, CT 06340, USA Available evidence indicates that clozapine is the most effective antipsychotic currently used for the pharmacotherapy of schizophrenia. Unfortunately, clozapine can cause serious side effects that limit the use of the drug. The therapeutic mechanism of action of clozapine is poorly understood, and accordingly, it has been difficult to design new drugs with the advan- tageous therapeutic properties of clozapine. Based on hypotheses that dopaminergic and ser- otonergic receptor-blocking properties of clozapine account for its clinical efficacy, several novel antipsychotic drugs have been introduced recently. There is currently insufficient data to reach definitive conclusions regarding the efficacy of the newer ‘atypical’ antipsychotics in comparison to clozapine. However, most published studies, and general clinical impressions, suggest that none of the newer drugs are as effective as clozapine in treating patients resist- ant to typical antipsychotic drug therapy. The present paper briefly reviews the clinical experi- ence with the newer ‘atypical’ antipsychotic drugs and then discusses clinical and preclinical data potentially relevant to mechanisms of action of clozapine in relation to the NMDA receptor hypofunction hypothesis of schizophrenia. Keywords: clozapine; olanzapine; risperidone; ziprasidone; quetiapine; antipsychotic; schizophrenia; dopamine; NMDA The introduction of clozapine for the pharmacotherapy Table 1) but it is unclear whether actions at specific of schizophrenia represented a significant advance in serotonin, dopamine, or adrenergic receptors, alone or the treatment of this devastating mental illness. Cloza- in combination, account for its clinical efficacy. pine is superior to typical neuroleptic drugs (eg A number of specific hypotheses concerning mech- haloperidol) in treating positive and negative symp- anisms of action of clozapine have directed drug dis- toms, and is effective in many patients who are refrac- covery efforts and led to clinical trials of drugs with tory to typical antipsychotics.1–3 In addition, clozapine widely different receptor-binding characteristics. The does not induce the extrapyramidal side effects (EPS) clinical experience with drugs whose development commonly caused by the typical agents. Because of was inspired by clozapine will be briefly reviewed and these properties, clozapine was termed atypical and then actions of clozapine and other antipsychotic drugs represents the prototype drug of this class. Although will be addressed in the context of the NMDA hypo- clozapine is the most efficacious antipsychotic cur- function hypothesis of schizophrenia. rently available, serious side effects induced by the drug, including agranulocytosis, impose substantial Clinical experience with clozapine-inspired limitations on its use. Concerted research and develop- putative antipsychotics in relation to therapeutic ment efforts have been made to produce an antipsy- mechanisms of action chotic drug with the therapeutic advantages of cloza- pine, without the properties contributing to its serious One of the earliest hypotheses of clozapine’s mech- side effects. However, the specific pharmacological anism of action related to the D1 dopamine antagon- characteristics of clozapine that confer its therapeutic istic properties of the drug.4 Clozapine binds to D1 properties are poorly understood. Clozapine binds to a receptors in vitro with modest affinity (see Table 1) and diverse number of neurotransmitter receptors (see at therapeutic doses occupies approximately 40–50% of D1 receptors in humans.5 Based on the hypothesis that the D1 antagonistic properties of clozapine dis- tinguished it from the typical antipsychotic drugs, Correspondence: GE Duncan, PhD, Neuroscience Center, CB # 7250, University of North Carolina School of Medicine, Chapel selective D1 antagonists were developed as potential Hill, NC 27599–7250, USA. E-mail: gduncanȰcss.unc.edu antipsychotic agents. Unfortunately, such drugs were Received 3 March 1999; revised and accepted 10 May 1999 not effective and there were indications that selective Antipsychotic drug action in schizophrenia GE Duncan et al 419 Table 1 Affinity of antipsychotic drugs for human neurotransmitter receptors Receptor Clozapine Risperidone Olanzapine Ziprasidone Quetiapine Haloperidol M-100907 (Ki, nM) D1 290 580 52 130 1300 120 1800 D2 130 2.2 20 3.1 180 1.4 1800 D3 240 9.6 50 7.2 940 2.5 D4 47 8.5 50 32 2200 3.3 5-HT1A 140 210 2100 2.5 230 3600 Ͼ4700 5-HT1Da 1700 170 530 2.0 Ͼ5100 Ͼ5000 Ͼ5100 5-HT2A 8.9 0.29 3.3 0.39 220 120 0.3 5-HT2C 17 10 10 0.72 1400 4700 68 5-HT6 11 2000 10 76 4100 6000 7400 5-HT7 66 3.0 250 9.3 1800 1100 2000 ␣1 4.0 1.4 54 13 15 4.7 68 ␣2 33 5.1 170 310 1000 1200 2200 H1 1.8 19 2.8 47 8.7 440 83 m1 1.8 2800 4.7 5100 100 1600 Values are geometric means of at least three determinations. aBovine. D1 antagonists may have even exacerbated symptoms it is difficult to infer equal efficacy of the drugs from of schizophrenia and induced extrapyramidal side the study of Bondolfi et al.14 Further investigation is effects.6,7 Although selective D1 antagonists were not necessary to adequately compare the relative efficacy effective, it is possible that D1 antagonistic properties of risperidone and clozapine in treatment-resistant of clozapine, in combination with other actions of the patients. drug, contribute to, but are not sufficient for, its thera- The reduced EPS side effects associated with low peutic effects. dose risperidone treatment (4–6 mg day−1), even at high Clozapine has relatively high affinity for 5HT2A levels of D2 receptor occupancy, may be due to the receptors and is a potent antagonist of 5HT2A receptor- 5HT2A antagonistic properties of the drug.10,15 How- mediated responses in vivo.8,9 The hypothesis has been ever, at higher doses, risperidone produces EPS, indi- advanced that the combination of relatively high affin- cating that 5HT2A receptor antagonism alone cannot ity for 5HT2A receptors, and lower affinity for D2 completely eliminate EPS associated with high D2 receptors, account for the atypical therapeutic actions receptor blockade. The potential role of 5HT2A recep- of clozapine and other atypical antipsychotics.10 The tor antagonism in therapeutic responses to atypical balanced D2/5HT2 hypothesis was the driving force antipsychotic drugs may become more apparent when behind development of risperidone, which is a potent data from clinical trials are available for the selective D2 and 5HT2 antagonist, but with greater relative 5HT2A antagonists M100907. affinity for the 5HT2A receptor (Table 1). Consistent Risperidone, like clozapine, has relatively high with the receptor-binding characteristics of risperi- affinity for alpha-1 and alpha-2 adrenergic receptors. done, high occupancy of D2 and 5HT2 receptors is The potential therapeutic significance of the adrenergic observed clinically at therapeutic doses.11 receptor-blocking properties of clozapine and risperi- Although risperidone is an effective antipsychotic done are uncertain. Addition of the alpha-2 antagonist agent, and has a favorable side effect profile in com- idazoxan to the regime of patients treated with the typi- parison to haloperidol, the general clinical impression cal neuroleptic fluphenazine improved treatment has been that risperidone is not as effective as cloza- responses in patients refractory to treatment with flu- pine in schizophrenic patients resistant to treatment phenazine alone.16 However, there has been no con- with typical antipsychotics. However, there is insuf- firmation of the effects of alpha-2 antagonists as ficient clinical data available to unequivocally estab- adjuncts to typical neuroleptic treatment and it has lish the superior efficacy of clozapine relative to risper- been suggested that alpha-2 agonists may actually be idone (for review see 3). Flynn et al12 and Breier et al13 useful for treating cognitive deficits of the disease.17 found that clozapine was more effective than risperi- Based on findings of elevated D3 dopamine receptors done in treatment-resistant patients. However, Bon- in drug-free schizophrenics, and a reduction in these dolfi et al found no difference between risperidone and receptors in patients treated with antipsychotics, Gure- clozapine in treatment-resistant patients.14 In this latter vich et al18 have suggested that normalization of D3 study, certain methodological issues may have led to receptors may be contribute to the efficacy of antipsy- an overestimation of the efficacy of both clozapine and chotic drugs. While risperidone and haloperidol are risperidone in truly resistant patients.3 Consequently, relatively potent D3 antagonists (Table 1), the affinity Antipsychotic drug action in schizophrenia GE Duncan et al 420 of clozapine for the D3 receptor is even lower than that doses of risperidone and olanzapine produce high for the D2 receptor. Thus antagonism of D3 receptors occupancy of D2 receptors suggest that D2 receptor by haloperidol and the newer ‘atypical’ drugs could antagonism could be a predominant
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