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Time course of antipsychotic treatment response in schizophrenia: Results from a naturalistic study in 280 patients
Schizophrenia Research 118 (2010) 183–188
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Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Time course of antipsychotic treatment response in schizophrenia: Results from a naturalistic study in 280 patients M. Jäger a,b,⁎, M. Riedel a, M. Obermeier a, R. Schennach-Wolff a, F. Seemüller a, T. Messer c, G. Laux d, H. Pfeiffer e, D. Naber f, L.G. Schmidt g, W. Gaebel h, J. Klosterkötter i, I. Heuser j, K.-U Kühn k, M.R. Lemke l, E. Rüther m, S. Klingberg n, M. Gastpar o, R. Bottlender a, H.-J. Möller a a
Department of Psychiatry, Ludwig-Maximilians-University, Nussbaumstr. 7, D-80336 Munich, Germany Department of Psychiatry II, Ulm University, Ludwig-Heilmeyer-Str. 2, D-89312 Günzburg, Germany c Psychiatric Clinic, District Hospital Augsburg, Dr. Mack-Str. 1, D-86156 Augsburg, Germany d Psychiatric Clinic, Inn-Salzach Hospital, Gabersee 7, 83512 Wasserburg/Inn, Germany e Psychiatric Clinic, Isar-Amper Hospital, Munich-East, Vockestr. 73, D-85540 Haar, Germany f Department of Psychiatry, University of Hamburg, Martinistr. 52, D-20246 Hamburg, Germany g Department of Psychiatry, Johannes-Gutenberg University of Mainz, Untere Zahlbacher Str. 8, 55131 Mainz, Germany h Department of Psychiatry, Heinrich-Heine-University Düsseldorf, Bergische Landstr. 2, D-40629 Düsseldorf, Germany i Department of Psychiatry, University of Cologne, Kerpener Str. 62, D-50924 Cologne, Germany j Department of Psychiatry, Charité Berlin, Campus Benjamin Franklin, Chariteplatz 1, D-10117 Berlin, Germany k Department of Psychiatry, University of Bonn, Sigmund-Freud-Str. 27, D-53105 Bonn, Germany l Psychiatric Clinic, Alsterdorf Hospital, Alsterdorfer Markt, D-22297 Hamburg, Germany m Department of Psychiatry, University of Göttingen, von Siebold Str. 5, D-37075 Göttingen, Germany n Department of Psychiatry, University of Tübingen, Osianderstr. 24, D-72076 Tübingen, Germany o Department of Psychiatry, University of Essen, Virchowstr. 174, D-45147 Essen, Germany b
a r t i c l e
i n f o
Article history: Received 19 November 2009 Received in revised form 29 January 2010 Accepted 2 February 2010 Available online 23 February 2010 Keywords: Schizophrenia Treatment Remission Response
a b s t r a c t Objective: To describe the course of positive and negative symptoms during inpatient treatment and examine remission and response rates under routine clinical care conditions. Methods: Two hundred and eighty inpatients with schizophrenia (DSM-IV criteria) were assessed with the Positive and Negative Syndrome Scale (PANSS) at admission and at biweekly intervals until discharge from hospital. Remission was defined according to the symptom– severity component of the consensus criteria (Remission in Schizophrenia Working Group) as a rating of three or less in the relevant PANSS items at discharge, and response as a reduction of at least 20% in the PANSS total score from admission to discharge. Results: The mean duration of inpatient treatment was 54.8 days. Of the total sample, 78.5% achieved the criteria for response and 44.6% those for remission. Mean PANSS total scores decreased from 72.4 at admission to 52.5 at discharge (p b 0.001). A reduction in PANSS total scores was found from visit to visit, up to week 8. The most pronounced decline was observed within the first two weeks of treatment. Conclusion: Response rates were comparable to those found in efficacy studies, and remission rates were slightly higher. This may be explained by differences in the selection and the treatment of patients. Nevertheless, the findings might indicate that a complex naturalistic treatment approach is beneficial in terms of effectiveness. © 2010 Elsevier B.V. All rights reserved.
⁎ Corresponding author. Department of Psychiatry II, Ulm University, BKH Günzburg Ludwig-Heilmeyer-Str. 2, D-89312 Günzburg, Germany. Tel.: + 49 8221 96 2204; fax: + 49 8221 96 2737. E-mail address: [email protected] (M. Jäger). 0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2010.02.002
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1. Introduction Antipsychotic drugs have been used for more than a half century. It is generally accepted that one of their central properties is the blocking of dopamine at D2 receptors (Seeman and Lee, 1975). However, the precise mechanism of their action is unclear and the time course of treatment response is poorly understood. Recent analyses have shown that response to antipsychotic treatment occurs within the first weeks of treatment (Agid et al., 2003; Kapur et al., 2005; Leucht et al., 2005). These findings, however, challenge the classical hypothesis of a “delayed onset” of antipsychotic drug action. Knowledge about the time course of treatment response is important because it allows the development of appropriate individualized therapeutic strategies for patients suffering from schizophrenic disorders. Hitherto, existing data have been based on meta-analyses or re-analyses of clinical drug trials (Agid et al., 2003; Kapur et al., 2005; Leucht et al., 2005). Randomized controlled trials (RCTs) provide the most reliable data on the efficacy of antipsychotic compounds in schizophrenic disorders. But the generalization of these data is limited because of strict inclusion criteria and rigid treatment regimes. Therefore, the gap between data derived from RCTs and those from psychiatric practice might have been underestimated (Heerdink et al., 2004). The assessment of outcomes of a “real world population” in everyday clinical practice might contribute to a more comprehensive picture of treatment effectiveness and help to bridge this gap. Not only effectiveness studies like CATIE, but also results from naturalistic studies could help to establish realistic goals for the treatment of schizophrenic disorders (Möller, 2008). As yet, however, only a few studies have assessed outcomes of inpatients in a routine clinical setting (Cesková et al., 2005; Weinmann et al., 2008). Based on a large sample of inpatients suffering from an acute episode or exacerbation of schizophrenia, the present study examines the time course of antipsychotic treatment response under routine clinical care conditions. The aims were (i) to describe the change in mean scores for positive and negative symptoms over the course of inpatient treatment, and (ii) to examine the development of remission and response rates. 2. Subjects and methods 2.1. Subjects The sample stems from a multi-centre follow-up program within the German Research Network on Schizophrenia (Wölwer et al., 2003); the program was conducted at eleven psychiatric university hospitals (Aachen, Berlin, Bonn, Cologne, Düsseldorf, Essen, Göttingen, Hamburg, Mainz, Munich, and Tübingen) and three psychiatric district hospitals (Augsburg, Wasserburg-Gabersee, and Munich-East). Patients admitted to one of the 14 above mentioned hospitals between January 2001 and December 2004 were included in the program if they met the inclusion and exclusion criteria and gave written informed consent. To prevent centrum effects when applying statistical analyses, patients were randomly selected using computer software. Patients had to be diagnosed with a schizophrenic spectrum disorder (ICD-10: F20–F29; DSM-IV: 295.1–7, 297.1, 298.8, 298.9) and were aged between 18 and 65 years. Exclusion criteria were a major medical illness as the possible
cause of the psychiatric symptoms, head injury, and drug or alcohol dependence. All patients had given written informed consent to participate in the study. The study protocol was approved by the local ethics committees (Jäger et al., 2007). For the present analyses, only patients with the diagnosis of schizophrenia according to DSM-IV criteria (295.1, 295.2, 295.3, 295.6, and 295.9) were selected from the entire sample. Patients were treated under naturalistic conditions (e.g. pharmacological treatment with antipsychotics, psychosocial treatment like psychoeducation programs, social skill training, or family interventions). The individualized treatment regimes (e.g. sequential or combination therapy with antipsychotics) followed the current state of the art and treatment guidelines for schizophrenia (Falkai et al., 2005). 2.2. Assessment Clinical researchers interviewed the patients at admission and made a diagnosis according to the DSM-IV criteria (American Psychiatric Association, 1994) — using the German version of the Structured Clinical Interview for DSM-IV (SCID) (First et al., 1997; Wittchen et al., 1997). Psychopathological characteristics were assessed with the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) (Kay, 1991) and the 17-item version of the Hamilton Rating Scale for Depression (HAMD-17) (Hamilton, 1960). The PANSS, a widely used 30-item scale for assessing schizophrenic symptoms, is composed of three subscales: positive symptoms (items P1–P7), negative symptoms (items N1–N7), and general psychopathology (items G1–G16). Each item can be graduated on a seven-point scale (1–7). The PANSS total score ranges from 30 to 210, the positive and negative subscores from 7 to 49, and the general psychopathology subscore from 16 to 112. Ratings were performed within three days after admission, and repeated at biweekly intervals during the acute inpatient treatment phase and at discharge. All assessments were performed by research psychiatrists (n = 52). A good interrater-reliability was achieved in the initial training session for PANSS (ANOVA-ICC N 0.80). The high interrater reliability was maintained throughout the entire study period by conducting interactive, video-based, psychopathology rater-training sessions at regular intervals at every participating hospital. To further assure accurate and consistent documentation, the collected data were sent on a regular basis to the coordinating study center to be checked for completeness and coherence. 2.3. Analyses In order to get an impression of the course of positive and negative symptoms during inpatient treatment, graphs of the mean PANSS total scores at each visit from admission (week 0) to week 10 were plotted applying the last observation carried forward (LOCF) method. To examine the course of the PANSS total scores, a mixed regression model was performed using covariates of interest (first-episode schizophrenia vs. multipleepisode schizophrenia). The model included a random intercept and slope because the data were longitudinal. Furthermore, an autoregressive AR-1 process was included to analyze the internal correlation structure of the data. For a validation of this model, a 10-fold cross-validation was performed by using Pearson's correlation and the root mean square error (RMSE) as
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loss functions. Beside this model, PANSS total scores, PANSS subscores (for positive symptoms, negative symptoms, and general psychopathology), and HAMD-17 total scores at admission and discharge were compared by using paired t-tests. Using the symptom–severity component of the recently proposed standardized remission criteria (Andreasen et al., 2005), remission was defined as a PANSS rating of three or less in all of the following items at discharge: “delusions” (P1), “unusual thought contents” (G9), “hallucinatory behavior” (P3), “conceptual disorganization” (P2), “mannerism/posturing” (G5), “blunted affect” (N1), “social withdrawal” (N4) and “lack of spontaneity” (N6). Response was defined as at least 20% improvement in PANSS total score from admission to discharge (Emsley et al., 2006). For the calculation of the percentage reduction in PANSS total score, the 1–7 scoring system was converted to a 0–6 scale by subtracting the minimum score of 30 (Leucht et al., 2007; Obermeier et al., 2009). This subtraction leads to a change of the scale level from interval scale to ratio scale. From a statistical view only ratio scales are appropriate for calculations proportional outcome measures (Obermeier et al., 2009). Remission and response rates of first-episode patients were compared with those of multiple-episode patients using Fisher tests. All statistical analyses were performed using the statistical software package R 2.8.1 (R Development Core Team, 2008). A p-value of ≤0.05 was considered to be statistically significant. 3. Results 3.1. Sample and treatment characteristics In total, 474 patients with schizophrenic spectrum disorders (ICD-10: F20–F29; DSM-IV: 295.1–7, 297.1, 298.8, 298.9) were enrolled in the entire study program. Fifteen patients (3%) were excluded because of retrospective violation of inclusion criteria, 11 (2%) because of withdrawal of informed consent, and 20 (4%) because of incomplete information. A further 28 patients (6%) were excluded from the analysis because they were discharged from hospital within seven days after admission. Finally, 120 patients (25%) were not included in the present analyses because they did not fulfill the diagnostic criteria for DSM-IV schizophrenia (295.1, 295.2, 295.3, 295.6, and 295.9). The present sample therefore comprised 280 subjects. Sociodemographic characteristics, course of illness, and treatment characteristics are presented in Table 1. The mean duration of inpatient treatment was 54.8 days (+/−45.1), with a wide range of 7 to 431 days; 99% of the patients stayed in hospital until week 2, 81% until week 4, 59% until week 6, 45% until week 8, and 29% until week 10. Inversely, 1% of the patients were discharged from hospital earlier than week 2, 18% between week 2 and week 4, 22% between week 4 and week 6, 15% between week 6 and week 8, 15% between week 8 and week 10, and 29% after week 10.
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Table 1 Sample and treatment characteristics. Sociodemographic characteristics Age Gender Regular employment Retired Course of illness First-episode schizophrenia Duration of illness Age at onset of illness Number of previous hospitalizations Treatment characteristics Duration of inpatient treatment First-generation antipsychotics Second-generation antipsychotics Antidepressants Tranquilizers Mood stabilizers
35.0 years (+/−11.2) 60.0% male (n = 168) 37.6% (n = 105) 17.9% (n = 50) 22.9 % (n = 64) 7.8 years (+/−9.3) 27.1 years (+/−9.6) 3.2 (+/−5.7) 54.8 days (+/−45.1) 50.4% (n = 141) 78.2% (n = 219) 26.8% (n = 75) 70.0% (n = 196) 8.2% (n = 23)
Continuous variables are presented as means (+/−standard deviation), categorical variables as absolute frequencies and percentages.
general psychopathology (from 34.8 to 26.2, p b 0.001), and to a lesser degree for negative symptoms (from 18.5 to 15.4, p b 0.001). Thus, there was a more pronounced improvement in positive symptoms than in negative symptoms and general psychopathology. HAMD-17 total scores decreased from 10.9 at admission to 6.4 at discharge (p b 0.001). There was a decrease in the PANSS total score from each visit to the subsequent visit, up to week 8. After week 8 there was no further decrease. The most pronounced decline was observed between admission and week 2 (Fig. 1). In a further step, PANSS total scores of patients with firstepisode schizophrenia (n = 64) were compared with those of patients with multiple-episode schizophrenia (n = 216) (Fig. 2). First-episode patients showed a more pronounced decrease in the PANSS total score (from 70.5 to 46.3) than multiple-episode patients (from 72.6 to 54.1). However, the time course of treatment response in the two groups was quite comparable. The results of the mixed model showed quadratic score courses and differences between first-episode and multiple-
3.2. Course of antipsychotic treatment response PANSS total scores decreased from admission to discharge (from 72.4 to 52.5, p b 0.001). This was also true for the PANSS subscores for positive symptoms (from 19.1 to 10.9, p b 0.001),
Fig. 1. PANSS total scores during inpatient treatment (LOCF).
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Fig. 2. PANSS total scores during inpatient treatment: first-episode patients compared with multiple-episode patients (LOCF).
Fig. 3. PANSS total scores during inpatient treatment: patients with a high PANSS total score at admission compared with those with a low one (LOCF).
4. Discussion episode patients. The quadratic influence of time was highly significant, as was the difference between first- and multipleepisode schizophrenia. The model itself showed a good performance, with a correlation score of 0.84 between estimated and real values and an RSME of 11.0 (Table 2). Finally, the course of treatment response of patients with a high PANSS total score at admission (above median) was compared with that of patients with a low PANSS total score (below median) (Fig. 3). Patients with a high score at baseline showed a more pronounced decrease in the PANSS total score (from 88.0 to 59.2) than those with a low score at admission (from 57.2 to 46.0).
3.3. Remission and response rates
4.1. Sample The present study was designed within the German Research Network on Schizophrenia to close the gap between efficacy trials and clinical care (Wölwer et al., 2003). Outcomes of 280 inpatients suffering from schizophrenia and treated under naturalistic conditions were examined. The present analysis was restricted to the inpatient treatment period (mean duration: 54.8 days). This observed mean duration of inpatient stay is comparable to that found by Weinmann et al. (2008), who examined treatment characteristics and outcomes before and after the implementation of schizophrenia practice guidelines in a German psychiatric hospital and found only a slightly lower duration of hospitalization after guideline implementation (49.2 days before and 48.4 days after).
Remission and response rates are shown in Fig. 4. In total, 220 of 280 patients (78.5%) achieved response and 125 of 280 patients (44.6%) achieved remission. However, 32 of 280 patients (11.4%) already fulfilled remission criteria at admission. When these patients were excluded from the analysis, 50.4% of the patients achieved remission during inpatient treatment. The highest rates for both remission and response were found within the first 4 weeks of treatment (from admission to week 2, and from week 2 to week 4). First-episode patients showed higher remission rates than multiple-episode patients (61% vs. 39%, pb 0.001). However, no statistically significant differences in response rates were found (86% vs. 75%, p =0.161).
Table 2 Mixed regression model for the examination of PANSS total scores during inpatient treatment.
Intercept Time Time2 First-episode schizophrenia
Value
SE
81.1727 − 14.6513 1.5812 − 6.1138
1.8501 1.0585 0.1611 2.1994
t-value 47.12 − 13.85 9.82 − 2.78
p-value p b 0.001 p b 0.001 p b 0.001 p = 0.006
Fig. 4. Development of remission and response rates: percentage of patients who achieved remission or response.
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4.2. Effectiveness of antipsychotic treatment
4.4. Limitations
In our study, the remission rate (44.6%) was slightly higher than those of clinical drug trials: Beitinger et al. (2008) reanalyzed data of antipsychotic drug trials and found remission rates of 41.5% after 28 weeks of treatment and 41.8% after 52 weeks of treatment (LOCF analyses). Lower frequencies of symptomatic remission were reported by Zimmermann et al. (2009) (31.8%), Lasser et al. (2005) (32%), and Helldin et al. (2007) (38%). Higher cross-sectional symptom-remission rates than those found in our study were reported by van Os et al. (2006) (46%) and Wunderink et al. (2007) (48%). These differences can probably be explained by differences in sample selection (e.g. diagnostic criteria, number of first-episode patients, duration of illness, duration of treatment, etc.). Our study may have achieved a higher remission rate because a naturalistic design allows patients to be treated with individual, complex treatment regimes (e.g. sequential or combination therapy with antipsychotics), whereas in RCTs medication is strictly controlled. The response rate in our study (78.5%) is comparable to that reported by Emsley et al. (2006), who found that 76.6% of firstepisode patients suffering from schizophrenia and treated with risperidone or haloperidol (in an RCT) achieved a ≥20% reduction in PANSS total score. A similar response rate (74.5%) was reported by Weinmann et al. (2008) in a routine clinical care sample after implementation of schizophrenia practice guidelines. However, the comparison of response rates between studies is limited by the use of different PANSS cut-off scores to define response. Furthermore, the calculation of percentage PANSS reduction raises questions: in this study, we used the approach described by Leucht et al. (2007) and Obermeier et al. (2009) and subtracted the minimum score of 30 from the PANSS total score, i.e. we converted the 1–7 scoring system into a 0–6 system. Other authors, however, seem to renounce such a conversion (Emsley et al., 2006; Tollefson et al., 2001).
The major strength of the present study might also be its major limitation: there were broad inclusion and only a few exclusion criteria (major medical illness, head injury, and alcohol dependence). Another limitation is that patients were treated under naturalistic conditions and effects of medication were not controlled. Lastly, since remission was defined according to the symptom–severity component of the consensus criteria at discharge and response as a reduction in the PANSS total score of at least 20% from admission to discharge, the time to achieve remission or response depended on the duration of hospitalization. The duration of inpatient stay, however, depends not only on psychopathological symptoms but also on other factors, like preferences of patients or relatives.
4.3. Time course of antipsychotic treatment response The mean PANSS total scores decreased as early as week 2, and thereafter there was a further statistically significant reduction from visit to visit until week 8. The most pronounced reduction in PANSS total scores, however, was found within the first two weeks of treatment. As the present study had a naturalistic design and no control group, it is not possible to estimate the time course of placebo response. Thus, some of the symptom reduction may not have been drug induced but caused by other factors. Nevertheless, these findings challenge the traditional hypothesis of a “delayed onset” of antipsychotic drug action and lend further support to the “early onset hypothesis” (Agid et al., 2003; Kapur et al., 2005; Leucht et al., 2005). The “early onset hypothesis” is further supported by preclinical research: Li et al. (2007) recently examined the time course of antipsychotic effect using a conditioned avoidance response model in rats. They found an early onset decline in avoidance responding, which re-emerged when the treatment was stopped. On the other hand, Emsley et al. (2006) reported a widely varying time to antipsychotic response in a sample of patients with firstepisode schizophrenia. The present study also found a wide range of times to remission and response.
5. Conclusions To summarize, the treatment under naturalistic conditions of “real world” patients suffering from schizophrenia appears to be beneficial in terms of clinical effectiveness. However, a considerable number of patients despite achieving response fail to achieve symptom remission during inpatient treatment, underlining the need for optimizing current available treatment. On the other hand, the results of the present study might help to determine realistic expectations for the treatment of schizophrenic disorders. Role of the funding source The study was performed within the framework of the German Research Network on Schizophrenia, which is funded by the German Federal Ministry for Education and Research BMBF (grant 01 GI 0233). The BMBF had no further role in the study design; in the collection, analysis and the interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Contributors The German Research Network on Schizophrenia designed the study and wrote the protocol. Markus Jäger managed the literature searches and analyses and wrote the first draft of the manuscript. Michael Obermeier undertook the statistical analyses. All authors contributed to and have approved the final manuscript. Conflict of interest Wolfgang Gaebel has received speaker's honoraria and research grants from the following companies: AstraZeneca, Janssen-Cilag, Lilly, Servier. He is a member of the Scientific Advisory Board of: Janssen-Cilag, Lilly, Lundbeck, and Wyeth. Joachim Klosterkötter has received/is receiving research grants/support from, serves as a consultant, is on the advisory board for, or is a member of the speaker bureau for AstraZeneca, Bristol Myers Squibb, Glaxo Smith Kline, Janssen-Cilag, Lilly, Lundbeck, Novartis, Sanofi-Synthelabo/Aventis, and Wyeth. Markus Jäger has received honoraria and travel payments from AstraZeneca, Janssen-Cilag and Lilly. Thomas Messer is on the advisory board for, or is a member of the speaker bureau of, or received educational grants from Bristol Myers Squibb, Janssen-Cilag, Lilly, Lundbeck, AstraZeneca, Sanofi-Synthelabo, Bayer Health Care, Pfizer and Essex Pharma. Hans-Jürgen Möller has received/is receiving research grants/support from, serves as a consultant for or is on the advisory board for, or is a member of the speaker bureau for Astrazeneca, Bristol Myers Squibb, Lilly, Eisai, GlaxoSmithKline, Janssen-Cilag, Lundbeck, Merck, Novartis, Organon, Pfizer, Sanofi Aventis, Sepracor, Servier, Wyeth. Dieter Naber has received honoraria/grants from AstraZeneca, Bristol Myers Squibb, JanssenCilag, Lilly, Lundbeck, Otsuka, Pfizer, Sanofi-Synthelabo, Servier, and Wyeth Pharma. Michael Riedel has received research grants/support of has served as a consultant for AstraZeneca, Pfizer, Otsuka, and Janssen-Cilag. In the context of investigator initiated trials Michael Riedel received support from AstraZeneca and Pfizer. Eckart Rüther has received/is receiving research grants/support
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from, serves as a consultant or is on the advisory board for, or is a member of the speaker bureau for AstraZeneca, Janssen-Cilag, Bristol Myers Squibb, Lundbeck, Lilly, Pfizer, Wyeth, and Bayer-Vital. Markus Gastpar, Isabella Heuser, Stefan Klingberg, K.-U. Kühn, Gerd Laux, Michael Obermeier, Herbert Pfeiffer, Rebecca Schennach-Wolff, Lutz G. Schmidt and Florian Seemüller declare no conflict of interest. Acknowledgements The network study was conducted at 14 psychiatric hospitals: Aachen (P. Hoff, K. Podoll), Augsburg (M. Schmauß, T. Messer, M. Eichinger), Berlin (I. Heuser, M. Jockers-Scherübl), Bonn (W. Maier, K.-U. Kühn, M.R. Lemke, R. Hurlemann, W.P. Hornung, E. Rosen), Cologne (J. Klosterkötter, W. Huff), Düsseldorf (W. Gaebel, A. Klimke, M. Eickhoff, M. von Wilmsdorff), Essen (M. Gastpar, V. Reißner), Gabersee (G. Laux, B. Hermann, B. Plichta), Göttingen (E. Rüther, D. Degner), Munich (H.-J. Möller, R. Bottlender, M. Riedel, M. Jäger, C. Schorr, B. Schillinger, C. Mirlach), Munich-East (H. Pfeiffer, M. Albus, S. ScharfBüssing), Hamburg (D. Naber, D. Golks), Mainz (L.G. Schmidt, B. KaufmannGrebe), and Tübingen (G. Buchkremer, M. Mayenberger). The authors thank Jacquie Klesing for the English-language editing of the manuscript.
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Jäger, M., Riedel, M., Messer, T., Laux, G., Pfeiffer, H., Naber, D., Gaebel, W., Huff, W., Schmidt, L.G., Heuser, I., Buchkremer, G., Kühn, K.U., Lemke, M.R., Rüther, E., Gastpar, M., Bottlender, R., Strauß, A., Möller, H.J., 2007. Psychopathological characteristics and treatment response of first episode compared with multiple episode schizophrenic disorders. Eur. Arch. Psychiatry Clin. Neurosci. 257, 47–53. Kapur, S., Arenovich, T., Agid, O., Zipursky, R., Lindborg, S., Jones, B., 2005. Evidence of onset of antipsychotic effects within the first 24 hours of treatment. Am. J. Psychiatry 162, 939–946. Kay, S.R., 1991. Positive and negative syndromes in schizophrenia: assessment and research. Clinical and experimental psychiatry monography No. 5 Brunner/Mazel, New York. Lasser, R.A., Bossie, C.A., Gharabawi, G.M., Kane, J.M., 2005. Remission in schizophrenia: results from a 1-year study of long-acting risperidone injection. Schizophr. Res. 77, 215–227. Leucht, S., Busch, R., Hamann, J., Kissling, W., Kane, J.M., 2005. Early-onset hypothesis of antipsychotic drug action: a hypothesis tested confirmed and extended. Biol. Psychiatry 57, 1543–1549. Leucht, S., Davis, J.M., Engel, R.R., Kane, J.M., Wagenpfeil, S., 2007. Defining “response” in antipsychotic drug trials: recommendations for the use of scale-derived cutoffs. Neuropsychopharmacology 32, 1903–1910. Li, M., Fletcher, P.J., Kapur, S., 2007. Time course of the antipsychotic effect and the underlying behavioural mechanisms. Neuropsychopharmacology 32, 263–272. Möller, H.J., 2008. Do effectiveness (“real world”) studies on antipsychotics tell us the real truth? Eur. Arch. Psychiatry Clin. Neurosci. 258, 257–270. Obermeier, M., Mayr, A., Schennach-Wolff, R., Seemüller, F., Möller, H.J., Riedel, M., 2009. Should the PANSS be rescaled? Schizophr. Bull. doi:10.1093/ schbul/sbp124. R Development Core Team, 2008. R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN: 3-900051-07-0. http://www.R-project.org. Seeman, P., Lee, T., 1975. Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 188, 1217–1219. Tollefson, D.G., Birkett, M.A., Kiesler, G.M., Wood, A.J., Lilly Resistant Schizophrenia Study Group, 2001. Double-blind comparison of olanzapine versus clozapine in schizophrenic patients clinically eligible for treatment with clozapine. Biol. Psychiatry 49, 52–63. Van Os, J., Drukker, M., á Campo, J., Meijer, J., Bak, M., Delespaul, P., 2006. Validation of remission criteria for schizophrenia. Am. J. Psychiatry 163, 2000–2002. Weinmann, S., Hoerger, S., Erath, M., Kilian, R., Gaebel, W., Becker, T., 2008. Implementation of a schizophrenia practice guideline. Clinical results. J. Clin. Psychiatry 69, 1299–1306. Wittchen, H.U., Wunderlich, U., Gruschwitz, S., Zaudig, M., 1997. Strukturiertes klinisches Interview für DSM-IV (SKID). Hogrefe, Göttingen. Wölwer, W., Buchkremer, G., Häfner, H., Klosterkötter, J., Maier, W., Möller, H.J., Gaebel, W., 2003. German research network on schizophrenia. Bridging the gap between research and care. Eur. Arch. Clin. Neurosci. 253, 321–329. Wunderink, L., Nienhuis, F.J., Sytema, S., Wiersma, D., 2007. Predictive validity of proposed remission criteria in first-episode schizophrenic patients responding to antipsychotics. Schizophr. Bull. 33, 792–796. Zimmermann, J., Wolter, A., Hannöver, W., Krischke, N., 2009. Frequency of remission in schizophrenia patients at one year follow-up. Psychiatr. Prax. 36, 182–188.
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Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Time course of antipsychotic treatment response in schizophrenia: Results from a naturalistic study in 280 patients M. Jäger a,b,⁎, M. Riedel a, M. Obermeier a, R. Schennach-Wolff a, F. Seemüller a, T. Messer c, G. Laux d, H. Pfeiffer e, D. Naber f, L.G. Schmidt g, W. Gaebel h, J. Klosterkötter i, I. Heuser j, K.-U Kühn k, M.R. Lemke l, E. Rüther m, S. Klingberg n, M. Gastpar o, R. Bottlender a, H.-J. Möller a a
Department of Psychiatry, Ludwig-Maximilians-University, Nussbaumstr. 7, D-80336 Munich, Germany Department of Psychiatry II, Ulm University, Ludwig-Heilmeyer-Str. 2, D-89312 Günzburg, Germany c Psychiatric Clinic, District Hospital Augsburg, Dr. Mack-Str. 1, D-86156 Augsburg, Germany d Psychiatric Clinic, Inn-Salzach Hospital, Gabersee 7, 83512 Wasserburg/Inn, Germany e Psychiatric Clinic, Isar-Amper Hospital, Munich-East, Vockestr. 73, D-85540 Haar, Germany f Department of Psychiatry, University of Hamburg, Martinistr. 52, D-20246 Hamburg, Germany g Department of Psychiatry, Johannes-Gutenberg University of Mainz, Untere Zahlbacher Str. 8, 55131 Mainz, Germany h Department of Psychiatry, Heinrich-Heine-University Düsseldorf, Bergische Landstr. 2, D-40629 Düsseldorf, Germany i Department of Psychiatry, University of Cologne, Kerpener Str. 62, D-50924 Cologne, Germany j Department of Psychiatry, Charité Berlin, Campus Benjamin Franklin, Chariteplatz 1, D-10117 Berlin, Germany k Department of Psychiatry, University of Bonn, Sigmund-Freud-Str. 27, D-53105 Bonn, Germany l Psychiatric Clinic, Alsterdorf Hospital, Alsterdorfer Markt, D-22297 Hamburg, Germany m Department of Psychiatry, University of Göttingen, von Siebold Str. 5, D-37075 Göttingen, Germany n Department of Psychiatry, University of Tübingen, Osianderstr. 24, D-72076 Tübingen, Germany o Department of Psychiatry, University of Essen, Virchowstr. 174, D-45147 Essen, Germany b
a r t i c l e
i n f o
Article history: Received 19 November 2009 Received in revised form 29 January 2010 Accepted 2 February 2010 Available online 23 February 2010 Keywords: Schizophrenia Treatment Remission Response
a b s t r a c t Objective: To describe the course of positive and negative symptoms during inpatient treatment and examine remission and response rates under routine clinical care conditions. Methods: Two hundred and eighty inpatients with schizophrenia (DSM-IV criteria) were assessed with the Positive and Negative Syndrome Scale (PANSS) at admission and at biweekly intervals until discharge from hospital. Remission was defined according to the symptom– severity component of the consensus criteria (Remission in Schizophrenia Working Group) as a rating of three or less in the relevant PANSS items at discharge, and response as a reduction of at least 20% in the PANSS total score from admission to discharge. Results: The mean duration of inpatient treatment was 54.8 days. Of the total sample, 78.5% achieved the criteria for response and 44.6% those for remission. Mean PANSS total scores decreased from 72.4 at admission to 52.5 at discharge (p b 0.001). A reduction in PANSS total scores was found from visit to visit, up to week 8. The most pronounced decline was observed within the first two weeks of treatment. Conclusion: Response rates were comparable to those found in efficacy studies, and remission rates were slightly higher. This may be explained by differences in the selection and the treatment of patients. Nevertheless, the findings might indicate that a complex naturalistic treatment approach is beneficial in terms of effectiveness. © 2010 Elsevier B.V. All rights reserved.
⁎ Corresponding author. Department of Psychiatry II, Ulm University, BKH Günzburg Ludwig-Heilmeyer-Str. 2, D-89312 Günzburg, Germany. Tel.: + 49 8221 96 2204; fax: + 49 8221 96 2737. E-mail address: [email protected] (M. Jäger). 0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2010.02.002
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1. Introduction Antipsychotic drugs have been used for more than a half century. It is generally accepted that one of their central properties is the blocking of dopamine at D2 receptors (Seeman and Lee, 1975). However, the precise mechanism of their action is unclear and the time course of treatment response is poorly understood. Recent analyses have shown that response to antipsychotic treatment occurs within the first weeks of treatment (Agid et al., 2003; Kapur et al., 2005; Leucht et al., 2005). These findings, however, challenge the classical hypothesis of a “delayed onset” of antipsychotic drug action. Knowledge about the time course of treatment response is important because it allows the development of appropriate individualized therapeutic strategies for patients suffering from schizophrenic disorders. Hitherto, existing data have been based on meta-analyses or re-analyses of clinical drug trials (Agid et al., 2003; Kapur et al., 2005; Leucht et al., 2005). Randomized controlled trials (RCTs) provide the most reliable data on the efficacy of antipsychotic compounds in schizophrenic disorders. But the generalization of these data is limited because of strict inclusion criteria and rigid treatment regimes. Therefore, the gap between data derived from RCTs and those from psychiatric practice might have been underestimated (Heerdink et al., 2004). The assessment of outcomes of a “real world population” in everyday clinical practice might contribute to a more comprehensive picture of treatment effectiveness and help to bridge this gap. Not only effectiveness studies like CATIE, but also results from naturalistic studies could help to establish realistic goals for the treatment of schizophrenic disorders (Möller, 2008). As yet, however, only a few studies have assessed outcomes of inpatients in a routine clinical setting (Cesková et al., 2005; Weinmann et al., 2008). Based on a large sample of inpatients suffering from an acute episode or exacerbation of schizophrenia, the present study examines the time course of antipsychotic treatment response under routine clinical care conditions. The aims were (i) to describe the change in mean scores for positive and negative symptoms over the course of inpatient treatment, and (ii) to examine the development of remission and response rates. 2. Subjects and methods 2.1. Subjects The sample stems from a multi-centre follow-up program within the German Research Network on Schizophrenia (Wölwer et al., 2003); the program was conducted at eleven psychiatric university hospitals (Aachen, Berlin, Bonn, Cologne, Düsseldorf, Essen, Göttingen, Hamburg, Mainz, Munich, and Tübingen) and three psychiatric district hospitals (Augsburg, Wasserburg-Gabersee, and Munich-East). Patients admitted to one of the 14 above mentioned hospitals between January 2001 and December 2004 were included in the program if they met the inclusion and exclusion criteria and gave written informed consent. To prevent centrum effects when applying statistical analyses, patients were randomly selected using computer software. Patients had to be diagnosed with a schizophrenic spectrum disorder (ICD-10: F20–F29; DSM-IV: 295.1–7, 297.1, 298.8, 298.9) and were aged between 18 and 65 years. Exclusion criteria were a major medical illness as the possible
cause of the psychiatric symptoms, head injury, and drug or alcohol dependence. All patients had given written informed consent to participate in the study. The study protocol was approved by the local ethics committees (Jäger et al., 2007). For the present analyses, only patients with the diagnosis of schizophrenia according to DSM-IV criteria (295.1, 295.2, 295.3, 295.6, and 295.9) were selected from the entire sample. Patients were treated under naturalistic conditions (e.g. pharmacological treatment with antipsychotics, psychosocial treatment like psychoeducation programs, social skill training, or family interventions). The individualized treatment regimes (e.g. sequential or combination therapy with antipsychotics) followed the current state of the art and treatment guidelines for schizophrenia (Falkai et al., 2005). 2.2. Assessment Clinical researchers interviewed the patients at admission and made a diagnosis according to the DSM-IV criteria (American Psychiatric Association, 1994) — using the German version of the Structured Clinical Interview for DSM-IV (SCID) (First et al., 1997; Wittchen et al., 1997). Psychopathological characteristics were assessed with the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) (Kay, 1991) and the 17-item version of the Hamilton Rating Scale for Depression (HAMD-17) (Hamilton, 1960). The PANSS, a widely used 30-item scale for assessing schizophrenic symptoms, is composed of three subscales: positive symptoms (items P1–P7), negative symptoms (items N1–N7), and general psychopathology (items G1–G16). Each item can be graduated on a seven-point scale (1–7). The PANSS total score ranges from 30 to 210, the positive and negative subscores from 7 to 49, and the general psychopathology subscore from 16 to 112. Ratings were performed within three days after admission, and repeated at biweekly intervals during the acute inpatient treatment phase and at discharge. All assessments were performed by research psychiatrists (n = 52). A good interrater-reliability was achieved in the initial training session for PANSS (ANOVA-ICC N 0.80). The high interrater reliability was maintained throughout the entire study period by conducting interactive, video-based, psychopathology rater-training sessions at regular intervals at every participating hospital. To further assure accurate and consistent documentation, the collected data were sent on a regular basis to the coordinating study center to be checked for completeness and coherence. 2.3. Analyses In order to get an impression of the course of positive and negative symptoms during inpatient treatment, graphs of the mean PANSS total scores at each visit from admission (week 0) to week 10 were plotted applying the last observation carried forward (LOCF) method. To examine the course of the PANSS total scores, a mixed regression model was performed using covariates of interest (first-episode schizophrenia vs. multipleepisode schizophrenia). The model included a random intercept and slope because the data were longitudinal. Furthermore, an autoregressive AR-1 process was included to analyze the internal correlation structure of the data. For a validation of this model, a 10-fold cross-validation was performed by using Pearson's correlation and the root mean square error (RMSE) as
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loss functions. Beside this model, PANSS total scores, PANSS subscores (for positive symptoms, negative symptoms, and general psychopathology), and HAMD-17 total scores at admission and discharge were compared by using paired t-tests. Using the symptom–severity component of the recently proposed standardized remission criteria (Andreasen et al., 2005), remission was defined as a PANSS rating of three or less in all of the following items at discharge: “delusions” (P1), “unusual thought contents” (G9), “hallucinatory behavior” (P3), “conceptual disorganization” (P2), “mannerism/posturing” (G5), “blunted affect” (N1), “social withdrawal” (N4) and “lack of spontaneity” (N6). Response was defined as at least 20% improvement in PANSS total score from admission to discharge (Emsley et al., 2006). For the calculation of the percentage reduction in PANSS total score, the 1–7 scoring system was converted to a 0–6 scale by subtracting the minimum score of 30 (Leucht et al., 2007; Obermeier et al., 2009). This subtraction leads to a change of the scale level from interval scale to ratio scale. From a statistical view only ratio scales are appropriate for calculations proportional outcome measures (Obermeier et al., 2009). Remission and response rates of first-episode patients were compared with those of multiple-episode patients using Fisher tests. All statistical analyses were performed using the statistical software package R 2.8.1 (R Development Core Team, 2008). A p-value of ≤0.05 was considered to be statistically significant. 3. Results 3.1. Sample and treatment characteristics In total, 474 patients with schizophrenic spectrum disorders (ICD-10: F20–F29; DSM-IV: 295.1–7, 297.1, 298.8, 298.9) were enrolled in the entire study program. Fifteen patients (3%) were excluded because of retrospective violation of inclusion criteria, 11 (2%) because of withdrawal of informed consent, and 20 (4%) because of incomplete information. A further 28 patients (6%) were excluded from the analysis because they were discharged from hospital within seven days after admission. Finally, 120 patients (25%) were not included in the present analyses because they did not fulfill the diagnostic criteria for DSM-IV schizophrenia (295.1, 295.2, 295.3, 295.6, and 295.9). The present sample therefore comprised 280 subjects. Sociodemographic characteristics, course of illness, and treatment characteristics are presented in Table 1. The mean duration of inpatient treatment was 54.8 days (+/−45.1), with a wide range of 7 to 431 days; 99% of the patients stayed in hospital until week 2, 81% until week 4, 59% until week 6, 45% until week 8, and 29% until week 10. Inversely, 1% of the patients were discharged from hospital earlier than week 2, 18% between week 2 and week 4, 22% between week 4 and week 6, 15% between week 6 and week 8, 15% between week 8 and week 10, and 29% after week 10.
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Table 1 Sample and treatment characteristics. Sociodemographic characteristics Age Gender Regular employment Retired Course of illness First-episode schizophrenia Duration of illness Age at onset of illness Number of previous hospitalizations Treatment characteristics Duration of inpatient treatment First-generation antipsychotics Second-generation antipsychotics Antidepressants Tranquilizers Mood stabilizers
35.0 years (+/−11.2) 60.0% male (n = 168) 37.6% (n = 105) 17.9% (n = 50) 22.9 % (n = 64) 7.8 years (+/−9.3) 27.1 years (+/−9.6) 3.2 (+/−5.7) 54.8 days (+/−45.1) 50.4% (n = 141) 78.2% (n = 219) 26.8% (n = 75) 70.0% (n = 196) 8.2% (n = 23)
Continuous variables are presented as means (+/−standard deviation), categorical variables as absolute frequencies and percentages.
general psychopathology (from 34.8 to 26.2, p b 0.001), and to a lesser degree for negative symptoms (from 18.5 to 15.4, p b 0.001). Thus, there was a more pronounced improvement in positive symptoms than in negative symptoms and general psychopathology. HAMD-17 total scores decreased from 10.9 at admission to 6.4 at discharge (p b 0.001). There was a decrease in the PANSS total score from each visit to the subsequent visit, up to week 8. After week 8 there was no further decrease. The most pronounced decline was observed between admission and week 2 (Fig. 1). In a further step, PANSS total scores of patients with firstepisode schizophrenia (n = 64) were compared with those of patients with multiple-episode schizophrenia (n = 216) (Fig. 2). First-episode patients showed a more pronounced decrease in the PANSS total score (from 70.5 to 46.3) than multiple-episode patients (from 72.6 to 54.1). However, the time course of treatment response in the two groups was quite comparable. The results of the mixed model showed quadratic score courses and differences between first-episode and multiple-
3.2. Course of antipsychotic treatment response PANSS total scores decreased from admission to discharge (from 72.4 to 52.5, p b 0.001). This was also true for the PANSS subscores for positive symptoms (from 19.1 to 10.9, p b 0.001),
Fig. 1. PANSS total scores during inpatient treatment (LOCF).
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Fig. 2. PANSS total scores during inpatient treatment: first-episode patients compared with multiple-episode patients (LOCF).
Fig. 3. PANSS total scores during inpatient treatment: patients with a high PANSS total score at admission compared with those with a low one (LOCF).
4. Discussion episode patients. The quadratic influence of time was highly significant, as was the difference between first- and multipleepisode schizophrenia. The model itself showed a good performance, with a correlation score of 0.84 between estimated and real values and an RSME of 11.0 (Table 2). Finally, the course of treatment response of patients with a high PANSS total score at admission (above median) was compared with that of patients with a low PANSS total score (below median) (Fig. 3). Patients with a high score at baseline showed a more pronounced decrease in the PANSS total score (from 88.0 to 59.2) than those with a low score at admission (from 57.2 to 46.0).
3.3. Remission and response rates
4.1. Sample The present study was designed within the German Research Network on Schizophrenia to close the gap between efficacy trials and clinical care (Wölwer et al., 2003). Outcomes of 280 inpatients suffering from schizophrenia and treated under naturalistic conditions were examined. The present analysis was restricted to the inpatient treatment period (mean duration: 54.8 days). This observed mean duration of inpatient stay is comparable to that found by Weinmann et al. (2008), who examined treatment characteristics and outcomes before and after the implementation of schizophrenia practice guidelines in a German psychiatric hospital and found only a slightly lower duration of hospitalization after guideline implementation (49.2 days before and 48.4 days after).
Remission and response rates are shown in Fig. 4. In total, 220 of 280 patients (78.5%) achieved response and 125 of 280 patients (44.6%) achieved remission. However, 32 of 280 patients (11.4%) already fulfilled remission criteria at admission. When these patients were excluded from the analysis, 50.4% of the patients achieved remission during inpatient treatment. The highest rates for both remission and response were found within the first 4 weeks of treatment (from admission to week 2, and from week 2 to week 4). First-episode patients showed higher remission rates than multiple-episode patients (61% vs. 39%, pb 0.001). However, no statistically significant differences in response rates were found (86% vs. 75%, p =0.161).
Table 2 Mixed regression model for the examination of PANSS total scores during inpatient treatment.
Intercept Time Time2 First-episode schizophrenia
Value
SE
81.1727 − 14.6513 1.5812 − 6.1138
1.8501 1.0585 0.1611 2.1994
t-value 47.12 − 13.85 9.82 − 2.78
p-value p b 0.001 p b 0.001 p b 0.001 p = 0.006
Fig. 4. Development of remission and response rates: percentage of patients who achieved remission or response.
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4.2. Effectiveness of antipsychotic treatment
4.4. Limitations
In our study, the remission rate (44.6%) was slightly higher than those of clinical drug trials: Beitinger et al. (2008) reanalyzed data of antipsychotic drug trials and found remission rates of 41.5% after 28 weeks of treatment and 41.8% after 52 weeks of treatment (LOCF analyses). Lower frequencies of symptomatic remission were reported by Zimmermann et al. (2009) (31.8%), Lasser et al. (2005) (32%), and Helldin et al. (2007) (38%). Higher cross-sectional symptom-remission rates than those found in our study were reported by van Os et al. (2006) (46%) and Wunderink et al. (2007) (48%). These differences can probably be explained by differences in sample selection (e.g. diagnostic criteria, number of first-episode patients, duration of illness, duration of treatment, etc.). Our study may have achieved a higher remission rate because a naturalistic design allows patients to be treated with individual, complex treatment regimes (e.g. sequential or combination therapy with antipsychotics), whereas in RCTs medication is strictly controlled. The response rate in our study (78.5%) is comparable to that reported by Emsley et al. (2006), who found that 76.6% of firstepisode patients suffering from schizophrenia and treated with risperidone or haloperidol (in an RCT) achieved a ≥20% reduction in PANSS total score. A similar response rate (74.5%) was reported by Weinmann et al. (2008) in a routine clinical care sample after implementation of schizophrenia practice guidelines. However, the comparison of response rates between studies is limited by the use of different PANSS cut-off scores to define response. Furthermore, the calculation of percentage PANSS reduction raises questions: in this study, we used the approach described by Leucht et al. (2007) and Obermeier et al. (2009) and subtracted the minimum score of 30 from the PANSS total score, i.e. we converted the 1–7 scoring system into a 0–6 system. Other authors, however, seem to renounce such a conversion (Emsley et al., 2006; Tollefson et al., 2001).
The major strength of the present study might also be its major limitation: there were broad inclusion and only a few exclusion criteria (major medical illness, head injury, and alcohol dependence). Another limitation is that patients were treated under naturalistic conditions and effects of medication were not controlled. Lastly, since remission was defined according to the symptom–severity component of the consensus criteria at discharge and response as a reduction in the PANSS total score of at least 20% from admission to discharge, the time to achieve remission or response depended on the duration of hospitalization. The duration of inpatient stay, however, depends not only on psychopathological symptoms but also on other factors, like preferences of patients or relatives.
4.3. Time course of antipsychotic treatment response The mean PANSS total scores decreased as early as week 2, and thereafter there was a further statistically significant reduction from visit to visit until week 8. The most pronounced reduction in PANSS total scores, however, was found within the first two weeks of treatment. As the present study had a naturalistic design and no control group, it is not possible to estimate the time course of placebo response. Thus, some of the symptom reduction may not have been drug induced but caused by other factors. Nevertheless, these findings challenge the traditional hypothesis of a “delayed onset” of antipsychotic drug action and lend further support to the “early onset hypothesis” (Agid et al., 2003; Kapur et al., 2005; Leucht et al., 2005). The “early onset hypothesis” is further supported by preclinical research: Li et al. (2007) recently examined the time course of antipsychotic effect using a conditioned avoidance response model in rats. They found an early onset decline in avoidance responding, which re-emerged when the treatment was stopped. On the other hand, Emsley et al. (2006) reported a widely varying time to antipsychotic response in a sample of patients with firstepisode schizophrenia. The present study also found a wide range of times to remission and response.
5. Conclusions To summarize, the treatment under naturalistic conditions of “real world” patients suffering from schizophrenia appears to be beneficial in terms of clinical effectiveness. However, a considerable number of patients despite achieving response fail to achieve symptom remission during inpatient treatment, underlining the need for optimizing current available treatment. On the other hand, the results of the present study might help to determine realistic expectations for the treatment of schizophrenic disorders. Role of the funding source The study was performed within the framework of the German Research Network on Schizophrenia, which is funded by the German Federal Ministry for Education and Research BMBF (grant 01 GI 0233). The BMBF had no further role in the study design; in the collection, analysis and the interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Contributors The German Research Network on Schizophrenia designed the study and wrote the protocol. Markus Jäger managed the literature searches and analyses and wrote the first draft of the manuscript. Michael Obermeier undertook the statistical analyses. All authors contributed to and have approved the final manuscript. Conflict of interest Wolfgang Gaebel has received speaker's honoraria and research grants from the following companies: AstraZeneca, Janssen-Cilag, Lilly, Servier. He is a member of the Scientific Advisory Board of: Janssen-Cilag, Lilly, Lundbeck, and Wyeth. Joachim Klosterkötter has received/is receiving research grants/support from, serves as a consultant, is on the advisory board for, or is a member of the speaker bureau for AstraZeneca, Bristol Myers Squibb, Glaxo Smith Kline, Janssen-Cilag, Lilly, Lundbeck, Novartis, Sanofi-Synthelabo/Aventis, and Wyeth. Markus Jäger has received honoraria and travel payments from AstraZeneca, Janssen-Cilag and Lilly. Thomas Messer is on the advisory board for, or is a member of the speaker bureau of, or received educational grants from Bristol Myers Squibb, Janssen-Cilag, Lilly, Lundbeck, AstraZeneca, Sanofi-Synthelabo, Bayer Health Care, Pfizer and Essex Pharma. Hans-Jürgen Möller has received/is receiving research grants/support from, serves as a consultant for or is on the advisory board for, or is a member of the speaker bureau for Astrazeneca, Bristol Myers Squibb, Lilly, Eisai, GlaxoSmithKline, Janssen-Cilag, Lundbeck, Merck, Novartis, Organon, Pfizer, Sanofi Aventis, Sepracor, Servier, Wyeth. Dieter Naber has received honoraria/grants from AstraZeneca, Bristol Myers Squibb, JanssenCilag, Lilly, Lundbeck, Otsuka, Pfizer, Sanofi-Synthelabo, Servier, and Wyeth Pharma. Michael Riedel has received research grants/support of has served as a consultant for AstraZeneca, Pfizer, Otsuka, and Janssen-Cilag. In the context of investigator initiated trials Michael Riedel received support from AstraZeneca and Pfizer. Eckart Rüther has received/is receiving research grants/support
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from, serves as a consultant or is on the advisory board for, or is a member of the speaker bureau for AstraZeneca, Janssen-Cilag, Bristol Myers Squibb, Lundbeck, Lilly, Pfizer, Wyeth, and Bayer-Vital. Markus Gastpar, Isabella Heuser, Stefan Klingberg, K.-U. Kühn, Gerd Laux, Michael Obermeier, Herbert Pfeiffer, Rebecca Schennach-Wolff, Lutz G. Schmidt and Florian Seemüller declare no conflict of interest. Acknowledgements The network study was conducted at 14 psychiatric hospitals: Aachen (P. Hoff, K. Podoll), Augsburg (M. Schmauß, T. Messer, M. Eichinger), Berlin (I. Heuser, M. Jockers-Scherübl), Bonn (W. Maier, K.-U. Kühn, M.R. Lemke, R. Hurlemann, W.P. Hornung, E. Rosen), Cologne (J. Klosterkötter, W. Huff), Düsseldorf (W. Gaebel, A. Klimke, M. Eickhoff, M. von Wilmsdorff), Essen (M. Gastpar, V. Reißner), Gabersee (G. Laux, B. Hermann, B. Plichta), Göttingen (E. Rüther, D. Degner), Munich (H.-J. Möller, R. Bottlender, M. Riedel, M. Jäger, C. Schorr, B. Schillinger, C. Mirlach), Munich-East (H. Pfeiffer, M. Albus, S. ScharfBüssing), Hamburg (D. Naber, D. Golks), Mainz (L.G. Schmidt, B. KaufmannGrebe), and Tübingen (G. Buchkremer, M. Mayenberger). The authors thank Jacquie Klesing for the English-language editing of the manuscript.
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