Treatment Response to Olanzapine and Haloperidol and its Association With Dopamine D 2. Receptor Occupancy in First-Episode Psychosis

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1 Original Research Treatment Response to Olanzapine and Haloperidol and its Association With Dopamine D 2 Receptor Occupancy in First-Episode Psychosis Robert B Zipursky, MD, FRCPC 1, Bruce K Christensen, PhD, CPsych 2, Zafiris Daskalakis, MD, PhD, FRCPC 3, Irvin Epstein, MD, FRCPC 3, Paul Roy, MD, FRCPC 4, Ivana Furimsky, RN, MN 5, Todd Sanger, PhD 6, Shitij Kapur, MD, PhD, FRCPC 7 Objective: Response to typical antipsychotic medication has been associated with achieving a level of striatal dopamine D 2 receptor occupancy in the range of 65% to 70%. We undertook this study to determine whether response to the atypical antipsychotic olanzapine occurs at lower levels of D 2 receptor occupancy. Method: Eighteen patients who presented with a first episode of psychosis were randomized to receive olanzapine 5 mg daily or haloperidol 2 mg daily in a double-blind design. We acquired positron emission tomography (PET) scans using the D 2 ligand [ 11 C]raclopride within the first 15 days of treatment to determine the percentage of D 2 receptors occupied by the medication. According to response, dosage was then adjusted to a maximum dosage of 20 mg daily of either drug. PET scans were repeated after 10 to 12 weeks of treatment. Results: At the first PET scan, the 8 olanzapine-treated patients had significantly lower D 2 receptor occupancies (mean 63.4%, SD 7.3) than those observed in the 10 patients treated with haloperidol (mean 73.0%, SD 6.1). When patients were rescanned following dosage adjustment, mean D 2 receptor occupancies were greater than 70% in both groups. D 2 receptor occupancies did not differ significantly between the olanzapine-treated group (mean 72.0%, SD 5.7) and the haloperidol-treated group (mean 78.7%, SD 7.6). Conclusions: These results suggest that, in patients being treated for a first episode of psychosis, olanzapine has its antipsychotic effect at approximately the same levels of D 2 receptor occupancy as are achieved with low dosages of haloperidol. (Can J Psychiatry 2005;50: ) Information on funding and support and author affiliations appears at the end of the article. Clinical Implications In patients receiving treatment for a first episode of psychosis, olanzapine has its antipsychotic effect at approximately the same levels of D 2 receptor occupancy as are achieved with low dosages of haloperidol. Clinical improvement of a first episode of psychosis is more likely to occur with both olanzapine and haloperidol if the dosage of medication results in peak levels of D 2 receptor occupancy above 70%. Once a sufficient level of D 2 receptor occupancy has been reached, the variability in clinical response observed is likely related to other factors. Limitations The small sample size limited this study s potential to investigate the association between D 2 receptor occupancy and clinical response and to detect small but potentially meaningful differences in the levels of D 2 receptor occupancy achieved with these medications. This study deals with only 2 antipsychotic medications, one typical and the other atypical. The patient sample involved individuals experiencing a first episode of psychosis who were willing to participate. It is not known whether these results can be generalized to other groups of patients with psychotic disorders. 462 Can J Psychiatry, Vol 50, No 8, July 2005

2 Treatment Response to Olanzapine and Haloperidol and its Association With Dopamine D 2 Receptor Occupancy in First-Episode Psychosis Abbreviations used in this article 5-HT BARS CGI CNS D 2 BP EPS PANSS PET SAS SCID SD SPECT serotonin Barnes Akathisia Rating Scale Clinical Global Impression central nervous system D 2 binding potential extrapyramidal symptoms Positive and Negative Syndrome Scale positron emission tomography Simpson Angus Scale Structured Clinical Interview for DSM-IV standard deviation single photon emission computed tomography Key Words: schizophrenia, first episode, positron emission tomography, PET, olanzapine, haloperidol, dopamine All currently available antipsychotic medications share the property of blocking dopamine D 2 receptors (1). Further, their relative antipsychotic potencies correlate well with their binding affinities with D 2 receptors in vitro (2). These findings have led to the suggestion that there may be a threshold level of D 2 receptor blockade necessary to bring about an antipsychotic response. Early studies failed to demonstrate any relation between the degree of D 2 receptor blockade and clinical response (3). However, the use of high dosages of typical antipsychotic medication and the resultant ceiling levels of D 2 receptor blockade might have precluded the possibility of demonstrating such an association. In addition, the inclusion of poorly responsive chronically ill subjects likely contributed to the difficulty of demonstrating such a relation. Studies by Nordstrom and others (4) and Kapur and others (5), using more modest dosages of raclopride and haloperidol, respectively, have now provided evidence that clinical response to typical antipsychotics requires blockade of approximately 65% to 70% of dopamine D 2 receptors. PET studies have demonstrated that clozapine, the classic atypical antipsychotic, has a very low affinity for the D 2 receptor: most clozapine-treated patients have steady-state levels of D 2 receptor blockade in the range of 20% to 60% (6,7). Given the increased number of new atypical antipsychotics now available, it has also become important to determine whether response to treatment with these agents might occur at a lower level of D 2 receptor occupancy. Uncontrolled PET studies, comparing different typical and atypical antipsychotics, have demonstrated that standard clinical dosages of the atypical antipsychotics risperidone and olanzapine result in levels of striatal D 2 receptor blockade that are comparable to those observed with low dosages of haloperidol (60% to 80%) (8 10). Several SPECT studies, however, have demonstrated that patients who are treated with olanzapine and sertindole may have lower levels of D 2 receptor occupancy than those receiving high dosages of haloperidol (11,12). Interpretation of previous studies is limited by methodological considerations: most were uncontrolled, did not randomize patients to different treatment groups, were based mainly on convenience samples, and used higher dosages of haloperidol. This last point is particularly crucial because many previous comparative studies used patients on dosages of haloperidol in the range of 10 mg daily, even though it is now clear that much lower dosages give adequate D 2 receptor occupancies. Our previous work demonstrated that patients receiving haloperidol for treatment of a first episode of schizophrenia were more likely to respond to treatment if more than 65% of D 2 receptors in the caudate were blocked (5,13,14). Such levels are usually achieved with haloperidol dosages in the range of 2 to 3 mg daily (14). Beyond this level, the risk of adverse side effects increases, with thresholds of approximately 72% and 78% D 2 receptor occupancy for prolactin elevation and EPS, respectively (5). Atypical antipsychotic agents have in part become increasingly popular for the treatment of first-episode schizophrenia because the risk of acute neurologic side effects appears to be lower with these medications (15 17). However, it is not known whether these agents are able to bring about improvement in these highly responsive patients at lower levels of D 2 receptor occupancy than are required for typical antipsychotics. Alternatively, it may be that equivalent degrees of D 2 receptor blockade are achieved but that other pharmacologic properties (that is affinity for 5-HT 2 or other neuroreceptors) are more relevant in explaining the differences in efficacy and side effects reported with these new medications (1). Using a randomized, double-blind design, we undertook this study to determine whether patients with a first episode of psychosis respond to the atypical antipsychotic olanzapine at lower levels of D 2 receptor occupancy than are observed with low dosages of haloperidol. Method This study was carried out as part of a randomized, double-blind, multicentre trial comparing the acute and long-term efficacy of olanzapine with haloperidol in patients experiencing a first episode of psychosis (18). Both male and female subjects were considered to be eligible for enrolment if they were aged between 16 and 40 years. The first onset of psychotic symptoms had to have occurred before age 35 years, and psychotic symptoms had to be present for at least 1 month, but no more than 5 years, prior to their entering the study. To be included, subjects were required to meet DSM-IV (19) criteria for schizophrenia, schizophreniform disorder, or Can J Psychiatry, Vol 50, No 8, July

3 The Canadian Journal of Psychiatry Original Research schizoaffective disorder as determined by the SCID (20). In addition, all subjects were required to be rated as having psychotic symptoms of moderate intensity on 2 or more of the following PANSS (21) psychosis items: delusions, conceptual disorganization, hallucinatory behaviour, grandiosity, or suspiciousness/persecution. Alternatively, they could have a rating of moderate severe intensity or greater on one of the items. Only subjects who were rated as moderately ill or greater on the CGI severity scale (22) were included. We excluded subjects if they had received more than 16 cumulative weeks of antipsychotic treatment in their lifetime, had serious unstable medical illnesses, had met DSM-IV criteria for substance dependence within the month prior to study entry, or had received injectable depot neuroleptics within fewer than 3 dosing intervals at the expected time of randomization. We also excluded subjects if they were receiving any medication having primarily CNS activity, with the following exceptions: lorazepam, diazepam, or chloral hydrate for agitation or insomnia; or benztropine, biperiden, or propranolol for EPS or akathisia. All subjects were recruited from the inpatient and outpatient services of the First Episode Psychosis Program at the Centre for Addiction and Mental Health, an urban teaching hospital fully affiliated with the University of Toronto. The Research Ethics Board of the Centre for Addiction and Mental Health approved the research protocol. The subjects received a complete description of the study and gave written informed consent to participate. At the Toronto site, 31 patients signed consent for the multicentre treatment study, of whom 18 elected to also participate in the PET protocol. Table 1 summarizes the subjects demographic and clinical characteristics. At the time of randomization, 9 subjects were neuroleptic-naive. The remainder underwent a brief washout period ranging from 2 days to 11 days (mean 5.9 days, SD 3.4 days). Patients were randomly assigned to receive 1 capsule daily of either drug (that is, 5 mg olanzapine or 2 mg haloperidol) for the first 2 weeks. After the second week in the trial, the dosage could be increased in a stepwise fashion to a maximum of 3 capsules daily (that is, for olanzapine, an increase from 5 mg to either 7.5 or 10 mg; and for haloperidol, an increase from 2 mg to either 4 or 6 mg). After the sixth week of the study, the dosages could be further increased over the next 6 weeks to a maximum dosage of 20 mg daily for either medication. We acquired the first PET scan after 6 to 15 days of treatment (mean 10.1 days, SD 2.8 days). We acquired the second PET scan 69 to 84 days after starting treatment (mean 73.0 days, SD 4.3 days). Clinical ratings were carried out following the 464 drug washout period and then weekly for the first 6 weeks and biweekly to the end of week 12. To rate psychopathology, we used the PANSS, which also provided measures of positive and negative symptom severity. We used the SAS to assess EPS (23) and the BARS to assess akathisia (24). We used prolactin levels determined at the time of randomization and at weeks 2 and 12 to investigate the relation between D 2 receptor occupancy and the change in plasma prolactin levels. PET scans to estimate dopamine D 2 receptor occupancy were obtained after the injection of 10 mci of high-specific-activity [ 11 C]raclopride (300 to 1600 Ci/mmol) through the use of a bolus plus infusion protocol and a GEMS B head-dedicated PET camera (General Electric Medical Systems, Milwaukee). The methods employed here are identical to those described in previous studies of haloperidol, loxapine, risperidone, olanzapine, quetiapine, and clozapine and have been published in detail before (13). We obtained an estimate of the dopamine D 2 BP of [ 11 C]raclopride from a ratio of the striatal to the cerebellar activity minus 1, in the 35- to 75-minute time period postinjection. In our laboratory, this method yields a within-subject scan rescan SD of 6% and is set up to yield a high interrater and intrarater reliability of > 0.95 (measured using the intraclass correlation coefficient). To calculate dopamine D 2 receptor occupancy, one requires a pretreatment estimate of available dopamine D 2 receptors. We used an age-corrected baseline derived from a separate sample of 12 antipsychotic-naive schizophrenia patients and 15 age-matched normal control subjects, as has been done in previous studies (10). Statistical Analyses We determined change in psychopathology at 2 weeks and at 12 weeks by calculating the difference in PANSS measures at those times, compared with the ratings completed immediately prior to randomization (Visit 2). For each measure, we calculated a percentage change measure by dividing the difference by the rating at Visit 2 and then multiplying by 100. To determine whether change in psychopathology was significant at the 2-week and 12-week points, we compared total PANSS scores, using 2-group Students t tests. Associations between the level of D 2 receptor occupancy and change in clinical measures were assessed with the Pearson product moment correlation coefficient. We used Fisher s exact test to determine whether there was a threshold level of D 2 receptor occupancy associated with clinical response. Results Of the 18 subjects who participated, 8 were randomized to receive olanzapine, and 10 were randomized to receive haloperidol. For the first 2 weeks of the study, all patients received 1 capsule daily of their respective study medications Can J Psychiatry, Vol 50, No 8, July 2005

4 Treatment Response to Olanzapine and Haloperidol and its Association With Dopamine D 2 Receptor Occupancy in First-Episode Psychosis Figure 1 Box plots showing D 2 receptor occupancies achieved on treatment with olanzapine and haloperidol as measured at Scan 1 and Scan 2. At Scan 1, all 8 olanzapine-treated patients were receiving 5 mg daily, and all 10 haloperidol-treated patients were receiving 2 mg daily. At Scan 2, the 6 olanzapine-treated patients were all receiving 10 mg daily, while the haloperidol-treated subjects were receiving a mean daily dosage of 4.4 mg (SD 4.8 mg) 90 %D 2 receptor occupancy olanzapine Scan 1 haloperidol Scan 1 olanzapine Scan 2 haloperidol Scan 2 (that is, olanzapine 5 mg daily or haloperidol 2 mg daily). Dosages were then modified as per the study protocol described above. We rescanned patients after 10 to 12 weeks of treatment. Of the 18 subjects who underwent the first scan, 13 returned for a repeat scan. Six of these subjects were receiving olanzapine, and 7 were receiving haloperidol. D 2 Receptor Occupancy Figure 1 shows D 2 receptor occupancy values measured at the first and second PET scans. At the time of the first PET scan, the mean D 2 receptor occupancy level for the 8 patients receiving olanzapine 5 mg daily was 63.4%, SD 7.3%, with a range of 53% to 73%. The 10 patients treated with haloperidol 2 mg daily had a mean D 2 receptor occupancy of 73.0%, SD 6.1%, with a range of 61% to 82%. The percentage of D 2 receptor occupancy was significantly higher in the haloperidol group (t = 3.0, df 16; P < 0.01). At the time of the second PET study, all 6 patients who were rescanned on olanzapine were receiving 10 mg daily; they had a mean D 2 receptor occupancy of 72.0%, SD 5.7%, with a range of 62% to 77%. Patients rescanned on haloperidol (mean 4.4 mg daily, SD 4.8, range 2 to 15 mg daily) had a mean occupancy of 78.7%, SD 7.6%, with a range of 64% to 89%. D 2 receptor occupancies for the 2 groups did not differ significantly following dosage adjustment (t = 1.8, df 11; P = 0.10). Response to Treatment Table 1 summarizes clinical measures at baseline. At baseline, the 2 treatment groups did not differ significantly on any of the PANSS measures. We observed significant improvement in psychopathology as measured by the PANSS total score at the 2-week rating in both the olanzapine-treated group (mean change 9.0, SD 14.5) and the haloperidol-treated group (mean change 15.2, SD 14.6). For those who continued through to the 12-week point of the study, we saw significant change for the 6 subjects on olanzapine (mean change 16.7, SD 23.8) and the 7 subjects on haloperidol (mean change 25.0, SD 15.1). Of the total 18 subjects studied with PET, 9 had experienced at least 20% improvement on the total PANSS at Week 2. Seven of 9 had D 2 occupancies of 70% or greater, whereas 6 of 9 who had less than 20% improvement had D 2 occupancies of less than 70%. Patients who had at least 70% of their receptors occupied were more likely to have experienced 20% improvement at the 2-week point (Fisher s exact test P = 0.08, 2-tailed); 70% (7/10) of individuals who had at least 70% of D 2 receptors occupied, compared with only 25% (2/8) of patients who had less than 70% of D 2 receptors occupied, experienced 20% improvement (Figure 2). For the total group of 18 patients at 2 weeks, changes in PANSS total, positive symptom, and negative symptom scores were not significantly correlated with D 2 receptor occupancy (r = 0.36, P = 0.14; r = 0.34, P = 0.17; and r = 0.36, P = 0.14, respectively). For the 10 subjects treated with haloperidol, D 2 receptor occupancy was correlated with the change on the PANSS total scores and PANSS negative scores (r = 0.68, P = 0.03; and r = 0.73, P = 0.02, Can J Psychiatry, Vol 50, No 8, July

5 The Canadian Journal of Psychiatry Original Research Table 1 Patient demographics and clinical severity measures at baseline Variable Olanzapine n =8 Haloperidol n =10 Age in years: mean (SD) 28.0 (6.2) 26.1 (5.9) Sex Ethnicity Men 7 9 Women 1 1 White 5 7 Black 0 1 Other 3 2 PANSS total: mean (SD) 70.5 (13.1) 78.1 (14.1) CGI: mean (SD) 4.1 (0.4) 4.4 (5.0) respectively), but not the PANSS positive scores (r = 0.32, P = 0.36). For the 8 subjects treated with olanzapine, the associations between D 2 receptor occupancy and PANSS total, PANSS positive, and PANSS negative symptoms scores were not statistically significant (r = 0.13, P = 0.76; r = 0.11, P = 0.79; and r = 0.06, P = 0.88, respectively). At 12 weeks, after dosages had been individually adjusted and all patients had D 2 occupancies of 62% or higher, no associations were found between D 2 receptor occupancy and change in PANSS total, PANSS positive, or PANSS negative scores for the 13 subjects remaining in the study (r = 0.00, P = 0.99; r = 0.17, P = 0.58; r = 0.06, P = 0.86, respectively). Side Effects Changes in prolactin levels were comparable for the olanzapine and haloperidol groups at both 2 weeks (mean 0.33 g/l, SD 0.41, and mean 0.35 g/l, SD 0.43, respectively) and 12 weeks (mean 0.27 g/l, SD 0.40 g/l, and mean 0.40 g/l, SD 0.40, respectively). Change in prolactin was significantly correlated with D 2 receptor occupancy at 12 weeks (n = 13, r = 0.60, P = 0.03) but not at 2 weeks (n = 18, r = 0.21, P = 0.41). At 12 weeks, this effect was apparent for the 7 subjects treated with haloperidol (r = 0.77, P = 0.04) but not for the 6 subjects treated with olanzapine (r = 0.33, P = 0.52). D 2 receptor occupancy was not significantly correlated with change on the SAS or the BARS at either the 2-week or 12-week points. Changes in SAS scores were greater in the haloperidol group than in the olanzapine group at both the 2-week ratings (mean 0.9, SD 2.0 vs mean 0.0, SD 0.5) and the 12-week ratings (mean 2.3, SD 4.8 vs mean 0.2, SD 0.4), but these differences were not statistically significant. Change on the BARS did not differ significantly between the haloperidol-treated and the olanzapine-treated groups at 2 weeks (mean 0.4, SD 1.0 vs mean 0.0, SD 0.5, respectively) or at 12 weeks (mean 0.0, SD 0.6 vs mean 0.0, SD 0.8). 466 Discussion This study s results suggest that, in patients receiving treatment for a first episode of psychosis, olanzapine has its antipsychotic effect at approximately the same levels of D 2 receptor occupancy as are achieved with low dosages of haloperidol. Thus, even though olanzapine acts on several neuroreceptors that haloperidol does not act on (for example 5-HT 2, histamine H 1, and muscarinic M 1 ), it still requires levels of D 2 receptor occupancy comparable to those achieved with haloperidol to achieve its antipsychotic effect. The dosages of medication that patients received over the first 2 weeks of the study (olanzapine 5 mg daily or haloperidol 2 mg daily) were not equivalent in the degree to which they occupied D 2 receptors: olanzapine produced lower levels of D 2 receptor occupancy. This is consistent with the recent study by de Haan and others, who used [ 123 I]iodobenzamide SPECT to demonstrate that olanzapine at a dosage of 7.5 mg daily resulted in less D 2 occupancy than did haloperidol at a dosage of 2.5 mg daily (25). To produce levels of D 2 occupancy equivalent to 2 mg daily of haloperidol, we would have required 10 mg daily of olanzapine (10). The choice of 5 mg daily of olanzapine vs 2 mg daily of haloperidol gave us the opportunity to see whether olanzapine could bring about antipsychotic response at lower levels of D 2 receptor occupancy than are seen with haloperidol at 2 mg daily. Our results suggest that this is not the case. Although there are certainly individuals who respond well to olanzapine at a dosage of 5 mg daily, our data suggest that response is more likely to happen, both with haloperidol and with olanzapine, if the dosage of medication results in peak levels of D 2 receptor occupancy above 70%. Both medications led to mean D 2 occupancies above 70% after dosage adjustment; however, there was a trend for subjects treated with olanzapine to have lower levels of D 2 receptor occupancy, compared with those treated with haloperidol. That this difference was not statistically significant may well be due to the very limited power of the study. However, it cannot be concluded that olanzapine brings about Can J Psychiatry, Vol 50, No 8, July 2005

6 Treatment Response to Olanzapine and Haloperidol and its Association With Dopamine D 2 Receptor Occupancy in First-Episode Psychosis Figure 2 Percentage of D 2 receptor occupancy vs percentage change in PANSS total score after 2 weeks of treatment with either olanzapine 5 mg daily (grey circles) or haloperidol 2 mg daily (black circles) % Change in PANSS %D 2 Occupancy clinical improvement at lower levels of D 2 receptor occupancy than does haloperidol because there was also a trend for the overall level of clinical improvement at 12 weeks to be lower in the olanzapine-treated group. It should also be noted that, while we do find an association between D 2 receptor occupancy and response in the first 2 weeks, we do not find such a relation at the 12-week mark. This is not surprising because, after the first 2 weeks, the clinicians were free to titrate the dosages individually in each patient to maximize response. This led to an increase in mean D 2 receptor occupancy in both groups, such that most patients in the study were above the putative threshold range for clinical response of 65% to 70% D 2 receptor occupancy. Thus it would seem that D 2 receptor occupancy may be an important first mediator of response but that, once a sufficient level of D 2 receptor occupancy has been reached, the rest of the variance in response is unrelated to the differences in D 2 receptor occupancy. This conclusion is consistent with the previous study by Wolkin and others, in which all patients were titrated to very high levels of D 2 receptor occupancy; as a result, differences in response were not related to D 2 receptor occupancy (3). Prolactin elevation and EPS are common adverse effects of antipsychotic treatment and are closely linked to the levels of D 2 receptor occupancy achieved (5). EPS have been observed in individuals treated with haloperidol, as well as with olanzapine and risperidone, when D 2 receptor occupancy reaches the 80% level (5). It was therefore surprising that we did not see a stronger relation between EPS and prolactin elevation and D 2 receptor occupancy. We think this is a function of the restricted dosage range of haloperidol used in our study. While almost all previous clinical studies have shown greater EPS and prolactin elevation with haloperidol, compared with olanzapine (26,27), all of them have also used dosages that give rise to a disproportionately higher level of D 2 receptor occupancy with haloperidol than with olanzapine. Several features make this study unique. They include the use of a randomized, double-blind design and a sample of newly diagnosed patients who would be expected to be highly responsive to treatment. The study is also strengthened by having had all subjects on a fixed dosage of medication during the first 2 weeks of the protocol. Interpretation of this study is, however, limited by the small sample size, the flexible dosage titration allowed in the protocol, and the fact that some participants had received previous antipsychotic treatment. The Can J Psychiatry, Vol 50, No 8, July

7 The Canadian Journal of Psychiatry Original Research question of the relative merits of olanzapine vs haloperidol in treating patients with a first episode of psychosis cannot be appropriately addressed with this small study; it is the subject of a previously published paper resulting from this multicentre study (18). Olanzapine has an effect on several receptors beyond the D 2 receptor system. Some of these, such as effects on the 5-HT 2 receptors, have been associated with a more beneficial effect on negative symptoms and on aspects of global improvement. In our study, we did not observe a preferential effect of olanzapine on negative symptoms or on total symptom improvement. This study s design relates primarily to the effects of olanzapine and haloperidol on D 2 receptors and is not optimal for assessing clinical effects that may be related to other neuroreceptors. A study design that involves a larger sample, a longer treatment duration, and greater variability in D 2 receptor occupancy and that is controlled across medications would help address this question more definitively. However, until such a study is done, the present data suggest that haloperidol and olanzapine require similar levels of D 2 receptor occupancy to induce an antipsychotic effect in patients early in the course of their psychotic illness. Funding and Support This work was supported by Eli Lilly and Co. Acknowledgements The authors acknowledge the contribution of the staff of the First Episode Psychosis Program at the Centre for Addiction and Mental Health, who provided care to the participants, and to the staff of the CAMH PET Centre for their invaluable technical assistance. References 1. Kapur S, Remington G. Dopamine D(2) receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry 2001;50: Seeman P, Lee T, Chau-Wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 1976;261: Wolkin A, Barouche F, Wolf AP, Rotrosen J, Fowler JS, Shiue CY, and others. Dopamine blockade and clinical response: evidence for two biological subgroups of schizophrenia. Am J Psychiatry 1989;146: Nordstrom A-L, Farde L, Wiesel FA, Forslund K, Pauli S, Halldin C, and others. Central D2-dopamine receptor occupancy in relation to antipsychotic drug effect: a double-blind PET study of schizophrenic patients. Biol Psychiatry 1993;33: Kapur S, Zipursky R, Jones C, Remington G, Houle S. Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 2000;157: Kapur S, Zipursky RB, Remington G. Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry 1999;156: Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall G. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine: relation to extrapyramidal side effects. Arch Gen Psychiatry 1992;49: Kapur S, Remington G, Zipursky RB, Wilson AA, Houle S. The D2-dopamine receptor occupancy of risperidone and its relationship to extrapyramidal symptoms: a PET study. Life Sci 1995;57: Kapur S, Zipursky RB, Remington G, Jones C, DaSilva J, Wilson AA, and others. 5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation. Am J Psychiatry 1998;155: Kapur S, Zipursky RB, Remington G. Clinical and therapeutic implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone and olanzapine in schizophrenia. Am J Psychiatry 1999;156: Pilowsky L, Busatto G, Taylor M, Costa D, Sharma T, Sigmundsson T, and others. Dopamine D2 receptor occupancy in vivo by the novel atypical antipsychotic olanzapine a 123I IBZM single photon emission tomography (SPET) study. Psychopharmacology (Berl) 1996;124: Pilowsky L, Mulligan R, Acton P, Ell P, Costa D, Kerwin R. Limbic selectivity of clozapine. Lancet 1997;350: Kapur S, Remington G, Jones C, Wilson A, DaSilva J, Houle S, and others. High levels of dopamine D2 receptor occupancy with low-dose haloperidol treatment: a PET study. Am J Psychiatry 1996;153: Kapur S, Zipursky RB, Roy P, Jones C, Remington G, Reed K, and others. The relationship between D2 receptor occupancy and plasma levels on low dose oral haloperidol: a PET study. Psychopharmacology (Berl) 1997;131: Kopala LC, Good KP, Honer WG. Extrapyramidal signs and clinical symptoms in first-episode schizophrenia: response to low-dose risperidone. J Clin Psychopharmacol 1997;17: Sanger TM, Lieberman JA, Tohen M, Grundy S, Beasley Jr C, Tollefson GD. Olanzapine versus haloperidol treatment in first-episode psychosis. Am J Psychiatry 1999;156: Emsley RA. Risperidone in the treatment of first-episode psychotic patients: a double-blind multicenter study. Schizophr Bull 1999;25: Lieberman JA, Tollefson G, Tohen M, Green AI, Gur RE, Kahn R, and others. Comparative efficacy and safety of atypical and conventional antipsychotic drugs in first-episode psychosis: a randomized double-blind trial of olanzapine versus haloperidol. Am J Psychiatry 2003;160: American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington (DC): American Psychiatric Association; First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition With Psychotic Screen (SCID-I/P W/ PSY SCREEN) New York: Biometrics Research, New York State Psychiatric Institute; Kay SR, Opler LA, Lindenmayer J-P. Reliability and validity of the Positive and Negative Syndrome Scale for schizophrenics. Psychiatr Res 1987;23: Guy W. ECDEU assessment manual for psychopharmacology. Revised ed. Rockville (MD): US Dept of Health, Education and Welfare, National Institute of Mental Health; Publication (ADM) Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 1970;212: Barnes T. A rating scale for drug induced akathisia. Br J Psychiatry 1989;154: de Haan L, van Bruggen M, Lavalaye J, Booij J, Dingemans PM, Linszen D. Subjective experience and D2 receptor occupancy in patients with recent-onset schizophrenia treated with low-dose olanzapine or haloperidol: a randomized, double-blind study. Am J Psychiatry 2003;160: Tollefson GD, Beasley CM, Tran PV, Street JS, Krueger JA, Tamura RN, and others. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry 1997;154: Beasley Jr CM, Tollefson G, Tran P, Satterlee W, Sanger T, Hamilton S, and others. Olanzapine versus placebo and haloperidol:acute phase results of the North American Double-Blind olanzapine trial. Neuropsychopharmacology 1996;14: Manuscript received October 2004 and accepted December Professor and Tapscott Chair in Schizophrenia Studies, Department of Psychiatry, University of Toronto, Toronto, Ontario; Clinical Director, Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ontario. 2 Assistant Professor, Department of Psychiatry, University of Toronto, Toronto, Ontario; Head, Neuropsychology Laboratory, Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ontario. 3 Assistant Professor, Department of Psychiatry, University of Toronto, Toronto, Ontario; Staff Psychiatrist, Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ontario. 4 Assistant Professor, Department of Psychiatry, University of Ottawa, Ottawa, Ontario; Staff Psychiatrist, Ottawa General Hospital, Ottawa, Ontario. 5 Research Coordinator, Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ontario. 6 Director, Global Statistical Sciences, Eli Lilly and Co, Indianapolis, Indiana. 7 Professor and Canada Research Chair in Schizophrenia and Therapeutic Neuroscience, Department of Psychiatry, University of Toronto, Toronto, Ontario; Chief of Research, Centre for Addiction and Mental Health, Toronto, Ontario. Address for correspondence: Dr RB Zipursky, Centre for Addiction and Mental Health, 250 College Street,Toronto, ON M5T 1R8 Robert_Zipursky@camh.net Can J Psychiatry, Vol 50, No 8, July 2005

8 Treatment Response to Olanzapine and Haloperidol and its Association With Dopamine D 2 Receptor Occupancy in First-Episode Psychosis Résumé : Réponse au traitement à l olanzapine et l halopéridol, et son association à l occupation des récepteurs D 2 de la dopamine, au premier épisode psychotique Objectif : La réponse à la médication antipsychotique typique a été associée à l atteinte d un niveau d occupation striatale des récepteurs D 2 de la dopamine, dans une échelle de 65 %à70%.nous avons entrepris cette étude pour déterminer si la réponse à l antipsychotique atypique olanzapine survient à des niveaux moins élevés d occupation des récepteurs D 2. Méthode : Dix-huit patients qui présentaient un premier épisode psychotique ont été choisis au hasard pour recevoir 5 mg d olanzapine par jour ou 2 mg d halopéridol par jour, dans une étude à double insu. Des tomographies par émission de positrons (TEP) sur le ligand D 2 [ 11 C]raclopride ont été obtenues dans les 15 premiers jours du traitement, pour déterminer le pourcentage de récepteurs D 2 occupés par le médicament. D après la réponse, le dosage était ensuite ajusté à un maximum de 20 mg par jour d un des deux médicaments. Les TEP étaient répétées après 10 à 12 semaines de traitement. Résultats : À la première TEP, les 8 patients traités à l olanzapine avaient des occupations significativement moins élevées des récepteurs D 2 (moyenne 63,4 %, ET 7,3) que celles observées chez les 10 patients traités à l halopéridol (moyenne 73,0 %, ET 6,1). Quand les patients ont subi de nouveau une tomographie, après ajustement du dosage, les occupations moyennes des récepteurs D 2 étaient supérieures à 70 %, dans les deux groupes. Les occupations des récepteurs D 2 ne différaient pas significativement entre le groupe traité à l olanzapine (moyenne 72,0 %, ET 5,7) et celui traité à l halopéridol (moyenne 78,7 %, ET 7,6). Conclusions : Ces résultats suggèrent que chez des patients traités pour un premier épisode psychotique, l olanzapine a un effet antipsychotique à peu près aux mêmes niveaux d occupation des récepteurs D 2 que ceux obtenus par de faibles doses d halopéridol. Can J Psychiatry, Vol 50, No 8, July