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Brief Report   |    
Time Course for Antipsychotic Treatment Response in First-Episode Schizophrenia
Robin Emsley, M.D.; Jonathan Rabinowitz, Ph.D.; Rossella Medori, M.D.
Am J Psychiatry 2006;163:743-745. doi:10.1176/appi.ajp.163.4.743

Abstract

Objective: The authors examined early onset of antipsychotic action and early prediction of nonresponse to antipsychotics in patients with first-episode schizophrenia. Method: Time to clinical response (≥20% improvement in total score on the Positive and Negative Syndrome Scale [PANSS]) was determined in 522 participants in a randomized, controlled trial comparing risperidone and haloperidol. Median treatment length was 206 days. Results: Clinical response was achieved in 77% (N=400) of subjects. Among these patients, clinical response was achieved in 23.3%, 23.3%, 18.5%, and 12.5% at weeks 1, 2, 3, and 4, respectively, after treatment initiation. However, in 22.5% of patients, response was not achieved until after 4 weeks, and in 11.2%, it was not achieved until after 8 weeks. In 45% of patients, response was achieved with a dose of 1–2 mg/day, in 27% with 3 mg/day, in 17% with 4 mg/day, and in the remaining 11% with higher doses. Improvement in the PANSS total score of at least 30%, 40%, and 50%, respectively, were achieved by 63.0%, 44.8%, and 27.5% of patients. Conclusions: Time to antipsychotic response varied widely, suggesting that, in first-episode schizophrenia, longer treatment trials may be necessary.

Abstract Teaser
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Early identification of nonresponders to antipsychotic treatment could prevent unnecessary persistence with ineffectual agents, thereby diminishing risk of adverse events. Reduced risk of adverse events could in turn reduce duration of hospitalization, level of care required, amounts of concomitant medication, and costs of care. Although most studies have examined putative response predictors before initiation of treatment, examination of symptom changes shortly after commencement of treatment may be a more reliable way of predicting response. Findings from a meta-analysis have challenged the belief that onset of action of antipsychotics is delayed by providing evidence for a robust early onset (13.8% reduction in symptom scores after 1 week) (1). This result suggests that response during the first week of treatment might provide an indication of how likely patients are to respond later in treatment. In keeping with earlier findings that early symptom changes could be a useful predictor of outcome (2), Correll et al. (3) investigated the predictive value of symptom changes 1 week after initiation of treatment. They found that early nonimprovement (<20% reduction in Brief Psychiatric Rating Scale total score at 1 week) predicted nonresponse at 4 weeks in 100% of cases, suggesting that treatment refractoriness may already be identifiable after 1 week.

Using data from a large multinational, randomized, double-blind trial comparing risperidone and haloperidol, we determined time to antipsychotic response in first-episode schizophrenia. We also examined as possible predictors of response previous antipsychotic exposure, duration of untreated psychosis, age, and sex.

The study methods have been described in more detail elsewhere (4). Patients with a diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder for ≥12 months were treated with 1 mg/day of either risperidone or haloperidol. The dose was increased if necessary by 1 mg/day after 3 days and weekly thereafter to a maximum dose of 4 mg/day. In exceptional cases (i.e., for subjects showing insufficient response in whom not more than mild extrapyramidal symptoms were observed at a dose of 4 mg/day), the dose could then be increased further by 1 mg/week up to a maximum daily dose of 8 mg. The mean modal dose was 3.3 mg/day for risperidone and 2.9 mg/day for haloperidol. The median length of treatment was 206 days (maximum of 1,514 days). Thirty-one percent (N=163) of the subjects had no previous exposure to antipsychotic medication. Clinical response was defined as a reduction of ≥20% in the Positive and Negative Syndrome Scale (PANSS) (5) total score.

Of the 522 patients, 400 (76.6%) achieved a ≥20% reduction in the PANSS total score. However, time to response varied considerably (Figure 1), with 93 (23.3%) patients achieving response during the first week of treatment, 93 (23.3%) at week 2, 74 (18.5%) at week 3, and 50 (12.5%) at week 4. Ninety (22.5%) of the patients did not respond until after the fourth week, and of those, 45 (11.5% of the 400 patients with a clinical response) did not respond until after the eighth week. The doses at times of response were 1 mg/day for 15.5% (N=62) of patients, 2 mg/day for 29.8% (N=119), 3 mg/day for 27.3% (N=109), 4 mg/day for 16.8% (N=67), and more than 4 mg/day for 10.8% (N=43).

Among the 522 patients, improvement of at least 20%, 30%, 40%, and 50%, respectively, on the PANSS total score was achieved by 76.6% (N=400), 63.0% (N=329), 44.8% (N=234), and 27.5% (N=144) of patients. Improvement of at least 20%, 30%, 40%, and 50%, respectively, was achieved by 72.9% (N=381), 59.6% (N=311), 44.6% (N=233), and 27.0% (N=141) of patients on the PANSS negative subscale, by 76.6% (N=400), 62.1% (N=324), 44.6% (N=233), and 28.9% (N=151) of patients on the PANSS general psychopathology subscale, and by 82.8% (N=432), 74.3% (N=388), 63.8% (N=333), and 48.5% (N=253) of patients (the most improvement) on the PANSS positive subscale.

Based on Cox regression analysis, which controlled for baseline PANSS score and study center, patients with previous antipsychotic exposure were less likely to respond (odds ratio=0.77, 95% confidence interval [CI]=0.61–0.97, p<0.03). Age, sex, and study medication were not significantly associated with response. For neuroleptic-naive patients (N=163, N=20 nonresponders), longer duration of untreated psychosis (log transformed) was associated with decreased likelihood of response (odds ratio=0.86, 95% CI=0.76–0.96, p=0.01).

The majority of the subjects in the study responded to antipsychotic treatment, in keeping with previously reported favorable response in first-episode schizophrenia (6). Our findings provide further evidence that, at least in some patients, onset of antipsychotic action is early—i.e., in the first week of treatment (1). However, time to response varied widely, with some responders achieving ≥20% improvement in PANSS total score only after more than 10 weeks of treatment. The median time to response in this group of patients was almost 3 weeks.

Our findings differ from those in a study of multiepisode patients by Correll et al. (3), as we did not find early nonresponse to be a reliable predictor of later nonresponse. Whereas Correll et al., using a somewhat different approach, found that all patients who failed to achieve 20% improvement after 1 week of treatment also failed to do so after 4 weeks of treatment, we found that 60% (N=256 of 424) of such patients (i.e., patients who had not improved after 1 week of treatment) were nonresponders at week 4. Moreover we found that of nonresponders at week 1 (N=424), 65.3% (N=277) went on to have a clinical response. Correll et al. found that 35% of those who had responded by week 1 were also responders at week 4; we found that 69.4% (N=68 of 98) of such patients were also responders at week 4.

If, as suggested in practice guidelines (7), treatment trial periods of 1 month or even 6 weeks were used for the subjects in our study, many patients would incorrectly have been regarded as nonresponders. Additional research is indicated, and if similar results emerge for other treatments, then practice guidelines recommending shorter durations of treatment (7) may need to be revised for first-episode psychosis. A possible explanation for the discrepant findings is that the study by Correll et al. (3) was of short duration (4 weeks). Also, in our study, a low-dosing strategy was adopted, which could explain slow response in some patients. We consider this explanation unlikely, however, as low doses of both risperidone (8) and haloperidol (9) have been shown to be at least as effective as high doses in first-episode psychosis. Our finding that shorter duration of untreated psychosis was a predictor of response is in keeping with previous work (10, 11).

The strengths of this study include large number of subjects, the fact that the subjects were first-episode patients, use of standardized assessment and diagnostic criteria, the ability to test treatment response for both a typical and an atypical antipsychotic, and the long treatment period. Flexible dosing design was both an advantage, in that it allowed mimicking of clinical practice, and a limitation, because time to response for a specific dose could not be examined. Future studies should examine the relationship between early symptom reduction and later overall outcome.

+Received Feb. 8, 2005; revisions received June 6 and Aug. 14, 2005; accepted Sept. 19, 2005. From the Department of Psychiatry, University of Stellenbosch, Tygerberg, Cape Town, South Africa; the Department of Social Work, Bar Ilan University; and Janssen-Cilag EMEA, Beerse, Belgium. Address correspondence and reprint requests to Dr. Rabinowitz, Department of Social Work, Bar Ilan University, Ramat Gan, Israel; rabinowz@mail.biu.ac.il (e-mail).Supported by Johnson & Johnson Pharmaceutical Research and Development. The study included the following locations and investigators: Australia—P. McGorry (Melbourne), T. Lambert (Bentley), J. Kulkarni (Dandenong); Austria—W. Fleischhacker (Innsbruck); Canada—D. Addington (Calgary), L. Kopala (Halifax), R. Williams (Calgary), G. Chouinard (Montreal), A. Labelle (Ottawa), A. Malla (London), S. Purdon (Edmonton), M. Saxena (Hamilton), V. Nair (Montreal), R. Matte (Sherbrooke), S. Johnson (St. John’s), L. Beauclair (Montreal); Finland—K. Lehtinen (Tampere); France—E.R. Lombertie (Limoges), J.-A. Meynard (La Rochelle); Germany—H. Freyberger (Stralsund), H.-J. Möller (Munich); Israel—A. Caspi and M. Davidson (Ramat-Gan), A. Elitzur (Bat-Yam), M. Kotler (Beer Sheva), I. Treves (Hod-Hasharon), A. Weizman (Petach-Tikva); the Netherlands—P. Dries (Poortugaal); New Zealand—D. Codyre (Auckland); South Africa—R. Emsley (Cape Town), C. Gagiano (Bloemfontein); United Kingdom—M. Reveley (Leicester), T. Sharma (London); United States—J. Csernansky (St. Louis), L. DeLisi (Stony Brook), J. Lauriello (Albuquerque), T. Manschreck (Fall River), J. Pahl (Oklahoma City), N Schooler and M. Keshavan (Pittsburgh), S. Schulz (Cleveland), S. Targum (Philadelphia), S. Risch (Charleston).

1. Agid O, Kapur S, Arenovich T, Zipursky RB: Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Arch Gen Psychiatry 2003; 60:1228–1235
 
2. May PR, Van Putten T, Yale C: Predicting outcome of antipsychotic drug treatment from early response. Am J Psychiatry 1980; 137:1088–1089
 
3. Correll CU, Malhotra AK, Kaushik S, McMeniman M, Kane JM: Early prediction of antipsychotic response in schizophrenia. Am J Psychiatry 2003; 160:2063–2065
 
4. Keshavan MS, Rabinowitz J, DeSmedt G, Harvey PD, Schooler N: Correlates of insight in first episode psychosis. Schizophr Res 2004; 70(2–3):187–194
 
5. Kay SR, Fiszbein A, Opler LA: The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13:261–276
 
6. Robinson DG, Woerner MG, Alvir JM, Geisler S, Koreen A, Sheitman B, Chakos M, Mayerhoff D, Bilder R, Goldman R, Lieberman JA: Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry 1999; 156:544–549
 
7. McEvoy JP, Scheifler PL, Frances A: The Expert Consensus Guidelines Series: Treatment of Schizophrenia. J Clin Psychiatry 1999; 60(suppl 11):1–80
 
8. Emsley RA: Risperidone in the treatment of first-episode psychotic patients: a double-blind multicenter study. Schizophr Bull 1999; 25:721–729
 
9. Oosthuizen P, Emsley R, Jadri Turner H, Keyter N: A randomized, controlled comparison of the efficacy and tolerability of low and high doses of haloperidol in the treatment of first-episode psychosis. Int J Neuropsychopharmacol 2004; 7:125–131
 
10. Ucok A, Polat A, Genc A, Cakiotar S, Turan N: Duration of untreated psychosis may predict acute treatment response in first-episode schizophrenia. J Psychiatr Res 2004; 38:163–168
 
11. Ho BC, Andreasen NC, Flaum M, Nopoulos P, Miller D: Untreated initial psychosis: its relation to quality of life and symptom remission in first-episode schizophrenia. Am J Psychiatry 2000; 157:808–815
 
 
Figure 1. Time Until ≥20% Reduction in Total Score on the Positive and Negative Syndrome Scale After Initiation of Treatment With Risperidone or Haloperidol Among 522 Patients With First-Episode Schizophrenia

Figure 1. Time Until ≥20% Reduction in Total Score on the Positive and Negative Syndrome Scale After Initiation of Treatment With Risperidone or Haloperidol Among 522 Patients With First-Episode Schizophrenia
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References

1. Agid O, Kapur S, Arenovich T, Zipursky RB: Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Arch Gen Psychiatry 2003; 60:1228–1235
 
2. May PR, Van Putten T, Yale C: Predicting outcome of antipsychotic drug treatment from early response. Am J Psychiatry 1980; 137:1088–1089
 
3. Correll CU, Malhotra AK, Kaushik S, McMeniman M, Kane JM: Early prediction of antipsychotic response in schizophrenia. Am J Psychiatry 2003; 160:2063–2065
 
4. Keshavan MS, Rabinowitz J, DeSmedt G, Harvey PD, Schooler N: Correlates of insight in first episode psychosis. Schizophr Res 2004; 70(2–3):187–194
 
5. Kay SR, Fiszbein A, Opler LA: The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13:261–276
 
6. Robinson DG, Woerner MG, Alvir JM, Geisler S, Koreen A, Sheitman B, Chakos M, Mayerhoff D, Bilder R, Goldman R, Lieberman JA: Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry 1999; 156:544–549
 
7. McEvoy JP, Scheifler PL, Frances A: The Expert Consensus Guidelines Series: Treatment of Schizophrenia. J Clin Psychiatry 1999; 60(suppl 11):1–80
 
8. Emsley RA: Risperidone in the treatment of first-episode psychotic patients: a double-blind multicenter study. Schizophr Bull 1999; 25:721–729
 
9. Oosthuizen P, Emsley R, Jadri Turner H, Keyter N: A randomized, controlled comparison of the efficacy and tolerability of low and high doses of haloperidol in the treatment of first-episode psychosis. Int J Neuropsychopharmacol 2004; 7:125–131
 
10. Ucok A, Polat A, Genc A, Cakiotar S, Turan N: Duration of untreated psychosis may predict acute treatment response in first-episode schizophrenia. J Psychiatr Res 2004; 38:163–168
 
11. Ho BC, Andreasen NC, Flaum M, Nopoulos P, Miller D: Untreated initial psychosis: its relation to quality of life and symptom remission in first-episode schizophrenia. Am J Psychiatry 2000; 157:808–815
 
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