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Analysis of resolution criteria in patients with schizophrenia treated with olanzapine for an acute psychotic episode
Schizophrenia Research 95 (2007) 169 – 173 www.elsevier.com/locate/schres
Analysis of resolution criteria in patients with schizophrenia treated with olanzapine for an acute psychotic episode Joseph Peuskens a,⁎, Leonard Kaufman b,1 , Betty Van Vleymen c a
b
Universitair Psychiatrisch Centrum Katholieke Universiteit Leuven, Campus St. Jozef Kortenberg, Leuvensesteenweg 517, 3070 Kortenberg, Belgium Vrije Universiteit Brussel, Eenheid Biostatistiek en Medische informatica, Laarbeeklaan 103, 1090 Jette, Belgium c Eli Lilly, Medical Department, Stoofstraat 52, 1000 Brussels, Belgium Received 3 November 2006; received in revised form 22 May 2007; accepted 25 May 2007 Available online 13 July 2007
Abstract Resolution was defined as achieving the severity component of the remission criteria (simultaneous ratings of mild or less on 8 of the PANSS items evaluating the core symptoms of schizophrenia). Analysis of a 6-week open label study with olanzapine 5– 20 mg in 306 patients with acute exacerbation, shows resolution to be a clinically meaningful measure and an achievable outcome for treatment of acute psychosis. © 2007 Published by Elsevier B.V. Keywords: Schizophrenia; Olanzapine; Remission; Resolution
1. Introduction Schizophrenia has been regarded as a long term, chronic illness with an inevitable deteriorating course and poor outcome. A dramatic improvement is often regarded as an evidence of misdiagnosis. Nevertheless improvements in pharmacological treatment and psychotherapeutic and psychosocial interventions offer the perspective to prevent the downward spiral. It was posited that symptomatic remission is a definable concept and an increasingly achievable stage in the treatment of schizophrenia (Andreasen et al., 2005). ⁎ Corresponding author. Tel.: +32 2 758 05 03; fax: +32 2 758 05 11. E-mail addresses: [email protected] (J. Peuskens), [email protected] (L. Kaufman), [email protected] (B. Van Vleymen). 1 Tel.: +32 2 477 47 24; fax: +32 2 477 40 00. 0920-9964/$ - see front matter © 2007 Published by Elsevier B.V. doi:10.1016/j.schres.2007.05.035
Furthermore a consensus on operational definition of symptomatic remission in schizophrenia is warranted to facilitate standardised comparisons across treatments and therapeutic modalities and to articulate more clearly expectations of patients, caregivers and mental health professionals on treatment outcome in schizophrenia. A number of definitions of remission have been proposed previously, in clinical research as well on first episode as on chronic schizophrenia, using different criteria concerning symptom severity, rating scales and duration. This variation makes comparisons of study results problematic (Lieberman et al., 1993; Liberman et al., 2002; Amminger et al., 1997; Eaton et al., 1998; Ho et al., 2000; Curtis et al., 2001; Yen et al., 2002; Leucht and Lasser, 2006). Recently remission criteria were described by Andreasen et al. (2005) that have been developed by a consensus in a large group of US and European
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J. Peuskens et al. / Schizophrenia Research 95 (2007) 169–173
clinicians and researchers. The definition of remission consists of two elements: a symptom based criterion uses a severity threshold of the core symptoms of schizophrenia (severity component) and a time criterion of 6 months (duration component). The working group choose to define symptomatic remission as “a state in which patients have experienced an improvement in core signs and symptoms to the extent that any remaining symptoms are of such low intensity that they no longer interfere significantly with behaviour and are below the threshold typically justifying the initial diagnosis of schizophrenia” (Andreasen et al., 2005). Core signs and symptoms are considered to be the diagnostic symptoms in the DSM IV aligning with the dimensions of psychopathology (disorganisation, psychoticism, psychomotor poverty) identified by factor analysis and supported by neurophysiological and neuroimaging measures and by longitudinal course. Also assessment scales were selected on which an operational definition of symptoms could be practically based. Using the Positive And Negative Syndrome Scale (PANSS) (Kay et al., 1987), the symptom based criterion is described as rating of mild or less (≤ 3) on each of the 8 diagnostically relevant core symptoms: delusions, unusual thought content, hallucinatory behaviour (psychoticism), conceptual disorganisation, mannerism/posturing (disorganisation), blunted affect, passive/apathetic social withdrawal, lack of spontaneity and flow of conversation (deficit symptom). This proposed definition of remission has been seen as conceptually viable and it may reset the expectations of treatment to a higher level, improve documentation of clinical status and facilitate dialogue on treatment expectations (Andreasen, 2006; Van Os et al., 2006). The analyses of trial data using the remission criteria indicate that they may represent a meaningful clinical endpoint (Sethuraman et al., 2005; Lasser et al., 2005). The use of absolute thresholds rather than percentage of improvement in clinical trials of acute psychosis will be more clinically relevant and facilitate comparisons between trials and treatments. It is not our aim to review remission criteria as such, but to add data to the growing literature on this remission definition and its use in clinical practice. The objective of our analysis is to evaluate whether the severity component of the remission criteria could be an achievable outcome and useful assessment of treatment of acute psychosis and introduce the terminology “resolution” or “cross sectional symptom” remission for achieving the remission criteria severity component without taking into account the time component. Furthermore we respond to the suggestion for further examination of the validity and utility of the remission consensus (Andreasen et al., 2005).
2. Subjects and methods 2.1. Study design This was an exploratory analysis of data derived from 306 patients with schizophrenia in a 6-week, open-label study evaluating the effect of olanzapine 5– 20 mg/day at a starting dose of 10 mg/day. Complete study details and results are reported elsewhere (Peuskens et al., 2004). The study was conducted in accordance with Good Clinical Practice and the Declaration of Helsinki. 2.2. Patients To be eligible for inclusion patients had to have an initial score of at least 42 on the Brief Psychiatric Rating Scale (BPRS) and a score of at least 4 on 2 or more items of the Positive and Negative Syndrome Scale (PANSS) positive subscale (items 1–7). Patients were mostly male (63%), on average 36 years old, met DSM-IV criteria for schizophrenia (74%), schizoaffective (16%) or schizophreniform disorder (10%). They had an initial mean PANSS of 102.8 (SD 20.0). 2.3. Assessments Patients were assessed with the PANSS at start of treatment, then weekly for the first 4 weeks and finally at 6 weeks.
Fig. 1. Percentage of improvement on the resolution score compared to baseline. Patients in resolution at week 6 (n = 112) are improving faster and more than those who don't achieve resolution (n = 147).
J. Peuskens et al. / Schizophrenia Research 95 (2007) 169–173
Response was defined as 20% improvement on PANSS positive score compared to baseline and maintained until week 6. Resolution was defined as achieving ratings of mild or less on the following 8 items in the PANSS: delusions, unusual thought content, hallucinatory behaviour, conceptual disorganisation, mannerisms/posturing, blunted affect, passive/apathetic social withdrawal and lack of spontaneity and flow of conversation. 2.4. Statistical analysis The intent-to-treat (ITT) population consisted of all patients initiated on treatment. Missing data were handled by last observation carried forward. The observed cases (OC) were all patients with available data at the time point of analysis. Mean, standard deviation and number of observations were used for PANSS score. Comparisons were performed by means of the paired t-test. All tests were performed two-tailed at the 5% level of significance. Correlations between scores are described by a Pearson Correlation Coefficient. 3. Results Compared with the response rate (20% improvement on PANNS positive score) at week 6, which was 62.7% (192/306) of the ITT patients and 74.1% (192/259) of the OC, resolution was achieved in 36.6% (112/306) of ITT patients and in 43.2% (112/259) of the OC. Also at week 6, a 20% improvement in the PANSS total score was seen in 55.2% (169/306) of the ITT patients and 65.2% (169/259) of the OC. Within the first week of treatment, 5.6% (17/306) achieved resolution. By weeks 2, 3, 4 and 6, the percentages had increased to 18.0%, 25.2%, 29.7% and 36.6% of ITT patients and were 5.8%, 19.9%, 29,2%, 37.0% and 43.2% of the OC. Of the 55 patients already in resolution at week 2, 47 were still so at week 6. One patient, with a total PANSS score of 85 at baseline, met the resolution criteria at baseline. At each week, the percentage of patients with 20% improvement on PANSS total score is higher than the patients in resolution. The ratio of 20% improvement vs. 20% improvement and resolution is decreasing (week 1–6: 3.1; 2.2; 1.9; 1.8; 1.6), because the number of patients in resolution is increasing while less new patients achieve 20% improvement. At each weekly evaluation 6 to 9 patients (2–3%) are in resolution without 20% improvement on the PANSS total score. The resolution sum score at baseline is correlated with the baseline score of the other PANSS items (r = 0.737)
171
and the clusters not represented in the resolution score (excitement (r = 0.365) and depression (r = 0.393), (p b 0.001)). The resolution score at week 6 remains significantly correlated with the other items of the PANSS (r = 0.356, p b 0.001) and weaker but still significantly with the other clusters not represented in the resolution score (excitement: r = 0.15; p = 0.016; depression r = 0.137; p b 0.028). A predictive factor for resolution at week 6 is lower total, positive, negative, general pathology or depressive PANNS scores at baseline. Patients who achieved resolution at week 6 showed a faster and more important improvement on all PANSS clusters (positive, negative, depressive, general pathology, excitement) (Fig. 1). Sixty patients discontinued the study, none of them while in resolution. Four of the patients who achieved resolution at week 2 discontinued the study before week 6, however while not in resolution. The reasons for discontinuation in these 4 patients were lack of efficacy (1), satisfactory response (1) and lost to follow up (2). 4. Discussion The results of our analysis indicate that the use of the resolution criteria could be an easy, useful and clinically meaningful measure to evaluate treatment in clinical trials of acute psychosis. First, patients can achieve resolution during short term treatment in the acute phase, as in this olanzapine trial 43.2% (112/259) of observed cases were in resolution after 6 weeks. Second, the resolution score is representative for PANSS total: there is a significant correlation between the resolution score and the other PANSS items and although weaker the clusters not represented in the resolution score (excitement and depression), indicating that the resolution score is mainly representative for the core symptoms and less for non-diagnostic symptoms of schizophrenia (Van Os et al., 2006). Third, using threshold criteria such as resolution allows to better study the effect on the core symptoms and comorbid symptoms separately. 20%, 30% or even 50% reduction is an arbitrary outcome definition: it depends on PANSS baseline, is not correlated with outcome in daily functioning and it describes a heterogeneous group of patients. Response rates increase over time as is the % of patients in resolution. However the % of patients in resolution is consistently lower since it is a more severe criterion: about 50% of responders do not achieve resolution within 6 weeks, 3% achieves resolution without 20% improvement and 1 patient was clinically diagnosed with an acute exacerbation while achieving the resolution criteria. This indicates that resolution and
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J. Peuskens et al. / Schizophrenia Research 95 (2007) 169–173
20% improvement are not measuring the same: Resolution is a threshold score and is a more robust and clinically meaningful outcome parameter compared to 20% improvement. A drug will be considered as efficacious in fewer patients. Another advantage of the use of resolution criteria is that the core symptoms of schizophrenia are evaluated: 20% reduction on the PANSS could mean that the patient is sedated, less anxious or depressed, but still very psychotic, disorganised or with severe negative symptoms. As such we propose to use the resolution criteria as an outcome in clinical trials of acute psychosis. Absolute thresholds reliably evaluated for instance with PANNS facilitate clinical interpretation and efficacy comparisons between trials and treatments. Within a week of treatment 5.6% of the patients achieved resolution and of those in resolution at week two, 85% (47/55) remained so at week 6, indicating that onset of antipsychotic action can be fast and robust (Kapur et al., 2005). Patients who achieve resolution show the largest symptom reduction during the first 3 weeks and continue to improve. Overall, patients not achieving resolution at week 6 were slow and poor responders in the first 4 weeks. It could be considered to switch these patients to another treatment because of possible interpatient variability in drug response. None of the 18.3% drop outs discontinued treatment while in resolution. Lack of disease insight and side effects are common reasons for patients to discontinue their treatment. These data also show that robust clinical improvement can motivate patients to continue treatment. In the CATIE study (Lieberman et al., 2005), most patients discontinued their initial treatment because of inefficacy (23%) compared to intolerability (15%). Also psychiatrists switched more patients to a different treatment because of inefficacy (20%, n = 283) and only 11% (n = 168) because of intolerability (McEvoy et al., 2006; Stroup et al., 2006). In conclusion: Resolution seems to be an achievable, easy, useful and clinically meaningful outcome measure for use in clinical trials of acute psychosis. Role of the funding source The open-label study was funded, designed and followed up by Eli Lilly Belgium. Contributors Joseph Peuskens designed the supplementary, exploratory analysis plan, Betty Van Vleymen managed literature searches and wrote the first draft and Leonard Kaufman undertook the statistical analysis. All authors contributed to the interpretation of the analyses and have approved the final manuscript.
Conflict of interest Joseph Peuskens received consultancy fees from Eli Lilly for various projects, Betty Van Vleymen is an employee of Eli Lilly Belgium and Leonard Kaufman received an honorarium for the statistical analysis.
References Amminger, G.P., Resch, F., Mutschlechner, R., Friedrich, M.H., Ernst, E., 1997. Premorbid adjustment and remission of positive symptoms in first-episode psychosis. Eur. Child Adolesc. Psychiatry 6 (4), 212–218. Andreasen, N.C., 2006. Standardized remission criteria in schizophrenia. Acta Psychiatr. Scand. 113 (2), 81. Andreasen, N.C., Carpenter Jr., W.T., Kane, J.M., Lasser, R.A., Marder, S.R., Weinberger, D.R., 2005. Remission in schizophrenia: proposed criteria and rationale for consensus. Am. J. Psychiatry 162, 441–449. Curtis, C.E., Calkins, M.E., Grove, W.M., Feil, K.J., Iacono, W.G., 2001. Saccadic disinhibition in patients with acute and remitted schizophrenia and their first-degree biological relatives. Am. J. Psychiatry 158 (1), 100–106. Eaton, W.W., Thara, R., Federman, E., Tien, A., 1998. Remission and relapse in schizophrenia: the Madras Longitudinal Study. J. Nerv. Ment. Dis. 186 (6), 357–363. Ho, B.C., Andreasen, N.C., Flaum, M., Nopoulos, P., Miller, D., 2000. Untreated initial psychosis: its relation to quality of life and symptom remission in first-episode schizophrenia. Am. J. Psychiatry 157 (5), 808–815. Kapur, S., Arenovich, T., Agid, O., Zipursky, R., Lindborg, S., Jones, B., 2005. Evidence for onset of antipsychotic effects within the first 24 hours of treatment. Am. J. Psychiatry 162 (5), 939–946. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13 (2), 261–276. Lasser, R.A., Bossie, C.A., Gharabawi, G.M., Kane, J.M., 2005. Remission in schizophrenia: results from a 1-year study of longacting risperidone injection. Schizophr. Res. 15, 215–227. Leucht, S., Lasser, R., 2006. The concepts of remission and recovery in schizophrenia. Pharmacopsychiatry 39, 161–170. Liberman, R.P., Kopelowicz, A., Ventura, J., Gutkind, D., 2002. Operational criteria and factors related to recovery from schizophrenia. Int. Rev. Psychiatry 14 (4), 256–272. Lieberman, J., Jody, D., Geisler, S., Alvir, J., Loebel, A., Szymanski, S., Worener, M., Borenstein, M., 1993. Time course and biologic correlates of treatment response in first-episode schizophrenia. Arch. Gen. Psychiatry 50 (5), 369–376. Lieberman, J.A., Stroup, T.S., McEvoy, J.P., Swartz, M.S., Rosenheck, R.A., Perkins, D.O., Keefe, R.S.E., Davis, S.M., Davis, C.E., Lebowitz, B.D., Severe, J., Hsiao, J.K., 2005. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N. Engl. J. Med. 353, 1209–1223. McEvoy, J.P., Lieberman, J.A., Stroup, T.S., Davis, S.M., Meltzer, H.Y., Rosenheck, R.A., Swartz, M.S., Perkins, D.O., Keefe, R.S.E., Davis, C.E., Severe, J., Hsiao, J.K., 2006. Effectiveness of Clozapine versus Olanzapine, Quetiapine, and Risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am. J. Psychiatry 163, 600–610. Peuskens, J., Mertens, C., Geerts, S., Gillain, B., Van Vleymen, B., 2004. Open study evaluating the onset of antipsychotic action of
J. Peuskens et al. / Schizophrenia Research 95 (2007) 169–173 olanzapine in the treatment of patients with schizophrenia, schizophreniform or schizoaffective disorder. Int. J. Psychiatry Clin. Pract. 8, 199–204. Sethuraman, G., Taylor, C.C., Enerson, M., Dunayevich, E.A., 2005. Retrospective comparison of cumulative time spent in remission during treatment with olanzapine or risperidone among patients with schizophrenia. Schizophr. Res. 15;79 (2–3), 337–340. Stroup, T.S., Lieberman, J.A., McEvoy, J.P., Swartz, M.S., Davis, S.M., Rosenheck, R.A., Perkins, D.O., Keefe, R.S.E., Davis, C.E., Severe, J., Hsiao, J.K., 2006. Effectiveness of Olanzapine,
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Quetiapine, Risperidone, and Ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am. J. Psychiatry 163, 611–622. Van Os, J., Burns, T., Cavallaro, R., Leucht, S., Peuskens, J., Helldin, L., Bernardo, M., Arango, C., Fleischhacker, W., Lachaux, B., Kane, J.M., 2006. Standardized remission criteria in schizophrenia. Acta Psychiatr. Scand. 113 (2), 91–95. Yen, C.F., Chen, C.S., Yeh, M.L., Ker, J.H., Yang, S.J., 2002. Comparison of insight in patients with schizophrenia and bipolar disorder in remission. J. Nerv. Ment. Dis. 190 (12), 847–849.
Analysis of resolution criteria in patients with schizophrenia treated with olanzapine for an acute psychotic episode Joseph Peuskens a,⁎, Leonard Kaufman b,1 , Betty Van Vleymen c a
b
Universitair Psychiatrisch Centrum Katholieke Universiteit Leuven, Campus St. Jozef Kortenberg, Leuvensesteenweg 517, 3070 Kortenberg, Belgium Vrije Universiteit Brussel, Eenheid Biostatistiek en Medische informatica, Laarbeeklaan 103, 1090 Jette, Belgium c Eli Lilly, Medical Department, Stoofstraat 52, 1000 Brussels, Belgium Received 3 November 2006; received in revised form 22 May 2007; accepted 25 May 2007 Available online 13 July 2007
Abstract Resolution was defined as achieving the severity component of the remission criteria (simultaneous ratings of mild or less on 8 of the PANSS items evaluating the core symptoms of schizophrenia). Analysis of a 6-week open label study with olanzapine 5– 20 mg in 306 patients with acute exacerbation, shows resolution to be a clinically meaningful measure and an achievable outcome for treatment of acute psychosis. © 2007 Published by Elsevier B.V. Keywords: Schizophrenia; Olanzapine; Remission; Resolution
1. Introduction Schizophrenia has been regarded as a long term, chronic illness with an inevitable deteriorating course and poor outcome. A dramatic improvement is often regarded as an evidence of misdiagnosis. Nevertheless improvements in pharmacological treatment and psychotherapeutic and psychosocial interventions offer the perspective to prevent the downward spiral. It was posited that symptomatic remission is a definable concept and an increasingly achievable stage in the treatment of schizophrenia (Andreasen et al., 2005). ⁎ Corresponding author. Tel.: +32 2 758 05 03; fax: +32 2 758 05 11. E-mail addresses: [email protected] (J. Peuskens), [email protected] (L. Kaufman), [email protected] (B. Van Vleymen). 1 Tel.: +32 2 477 47 24; fax: +32 2 477 40 00. 0920-9964/$ - see front matter © 2007 Published by Elsevier B.V. doi:10.1016/j.schres.2007.05.035
Furthermore a consensus on operational definition of symptomatic remission in schizophrenia is warranted to facilitate standardised comparisons across treatments and therapeutic modalities and to articulate more clearly expectations of patients, caregivers and mental health professionals on treatment outcome in schizophrenia. A number of definitions of remission have been proposed previously, in clinical research as well on first episode as on chronic schizophrenia, using different criteria concerning symptom severity, rating scales and duration. This variation makes comparisons of study results problematic (Lieberman et al., 1993; Liberman et al., 2002; Amminger et al., 1997; Eaton et al., 1998; Ho et al., 2000; Curtis et al., 2001; Yen et al., 2002; Leucht and Lasser, 2006). Recently remission criteria were described by Andreasen et al. (2005) that have been developed by a consensus in a large group of US and European
170
J. Peuskens et al. / Schizophrenia Research 95 (2007) 169–173
clinicians and researchers. The definition of remission consists of two elements: a symptom based criterion uses a severity threshold of the core symptoms of schizophrenia (severity component) and a time criterion of 6 months (duration component). The working group choose to define symptomatic remission as “a state in which patients have experienced an improvement in core signs and symptoms to the extent that any remaining symptoms are of such low intensity that they no longer interfere significantly with behaviour and are below the threshold typically justifying the initial diagnosis of schizophrenia” (Andreasen et al., 2005). Core signs and symptoms are considered to be the diagnostic symptoms in the DSM IV aligning with the dimensions of psychopathology (disorganisation, psychoticism, psychomotor poverty) identified by factor analysis and supported by neurophysiological and neuroimaging measures and by longitudinal course. Also assessment scales were selected on which an operational definition of symptoms could be practically based. Using the Positive And Negative Syndrome Scale (PANSS) (Kay et al., 1987), the symptom based criterion is described as rating of mild or less (≤ 3) on each of the 8 diagnostically relevant core symptoms: delusions, unusual thought content, hallucinatory behaviour (psychoticism), conceptual disorganisation, mannerism/posturing (disorganisation), blunted affect, passive/apathetic social withdrawal, lack of spontaneity and flow of conversation (deficit symptom). This proposed definition of remission has been seen as conceptually viable and it may reset the expectations of treatment to a higher level, improve documentation of clinical status and facilitate dialogue on treatment expectations (Andreasen, 2006; Van Os et al., 2006). The analyses of trial data using the remission criteria indicate that they may represent a meaningful clinical endpoint (Sethuraman et al., 2005; Lasser et al., 2005). The use of absolute thresholds rather than percentage of improvement in clinical trials of acute psychosis will be more clinically relevant and facilitate comparisons between trials and treatments. It is not our aim to review remission criteria as such, but to add data to the growing literature on this remission definition and its use in clinical practice. The objective of our analysis is to evaluate whether the severity component of the remission criteria could be an achievable outcome and useful assessment of treatment of acute psychosis and introduce the terminology “resolution” or “cross sectional symptom” remission for achieving the remission criteria severity component without taking into account the time component. Furthermore we respond to the suggestion for further examination of the validity and utility of the remission consensus (Andreasen et al., 2005).
2. Subjects and methods 2.1. Study design This was an exploratory analysis of data derived from 306 patients with schizophrenia in a 6-week, open-label study evaluating the effect of olanzapine 5– 20 mg/day at a starting dose of 10 mg/day. Complete study details and results are reported elsewhere (Peuskens et al., 2004). The study was conducted in accordance with Good Clinical Practice and the Declaration of Helsinki. 2.2. Patients To be eligible for inclusion patients had to have an initial score of at least 42 on the Brief Psychiatric Rating Scale (BPRS) and a score of at least 4 on 2 or more items of the Positive and Negative Syndrome Scale (PANSS) positive subscale (items 1–7). Patients were mostly male (63%), on average 36 years old, met DSM-IV criteria for schizophrenia (74%), schizoaffective (16%) or schizophreniform disorder (10%). They had an initial mean PANSS of 102.8 (SD 20.0). 2.3. Assessments Patients were assessed with the PANSS at start of treatment, then weekly for the first 4 weeks and finally at 6 weeks.
Fig. 1. Percentage of improvement on the resolution score compared to baseline. Patients in resolution at week 6 (n = 112) are improving faster and more than those who don't achieve resolution (n = 147).
J. Peuskens et al. / Schizophrenia Research 95 (2007) 169–173
Response was defined as 20% improvement on PANSS positive score compared to baseline and maintained until week 6. Resolution was defined as achieving ratings of mild or less on the following 8 items in the PANSS: delusions, unusual thought content, hallucinatory behaviour, conceptual disorganisation, mannerisms/posturing, blunted affect, passive/apathetic social withdrawal and lack of spontaneity and flow of conversation. 2.4. Statistical analysis The intent-to-treat (ITT) population consisted of all patients initiated on treatment. Missing data were handled by last observation carried forward. The observed cases (OC) were all patients with available data at the time point of analysis. Mean, standard deviation and number of observations were used for PANSS score. Comparisons were performed by means of the paired t-test. All tests were performed two-tailed at the 5% level of significance. Correlations between scores are described by a Pearson Correlation Coefficient. 3. Results Compared with the response rate (20% improvement on PANNS positive score) at week 6, which was 62.7% (192/306) of the ITT patients and 74.1% (192/259) of the OC, resolution was achieved in 36.6% (112/306) of ITT patients and in 43.2% (112/259) of the OC. Also at week 6, a 20% improvement in the PANSS total score was seen in 55.2% (169/306) of the ITT patients and 65.2% (169/259) of the OC. Within the first week of treatment, 5.6% (17/306) achieved resolution. By weeks 2, 3, 4 and 6, the percentages had increased to 18.0%, 25.2%, 29.7% and 36.6% of ITT patients and were 5.8%, 19.9%, 29,2%, 37.0% and 43.2% of the OC. Of the 55 patients already in resolution at week 2, 47 were still so at week 6. One patient, with a total PANSS score of 85 at baseline, met the resolution criteria at baseline. At each week, the percentage of patients with 20% improvement on PANSS total score is higher than the patients in resolution. The ratio of 20% improvement vs. 20% improvement and resolution is decreasing (week 1–6: 3.1; 2.2; 1.9; 1.8; 1.6), because the number of patients in resolution is increasing while less new patients achieve 20% improvement. At each weekly evaluation 6 to 9 patients (2–3%) are in resolution without 20% improvement on the PANSS total score. The resolution sum score at baseline is correlated with the baseline score of the other PANSS items (r = 0.737)
171
and the clusters not represented in the resolution score (excitement (r = 0.365) and depression (r = 0.393), (p b 0.001)). The resolution score at week 6 remains significantly correlated with the other items of the PANSS (r = 0.356, p b 0.001) and weaker but still significantly with the other clusters not represented in the resolution score (excitement: r = 0.15; p = 0.016; depression r = 0.137; p b 0.028). A predictive factor for resolution at week 6 is lower total, positive, negative, general pathology or depressive PANNS scores at baseline. Patients who achieved resolution at week 6 showed a faster and more important improvement on all PANSS clusters (positive, negative, depressive, general pathology, excitement) (Fig. 1). Sixty patients discontinued the study, none of them while in resolution. Four of the patients who achieved resolution at week 2 discontinued the study before week 6, however while not in resolution. The reasons for discontinuation in these 4 patients were lack of efficacy (1), satisfactory response (1) and lost to follow up (2). 4. Discussion The results of our analysis indicate that the use of the resolution criteria could be an easy, useful and clinically meaningful measure to evaluate treatment in clinical trials of acute psychosis. First, patients can achieve resolution during short term treatment in the acute phase, as in this olanzapine trial 43.2% (112/259) of observed cases were in resolution after 6 weeks. Second, the resolution score is representative for PANSS total: there is a significant correlation between the resolution score and the other PANSS items and although weaker the clusters not represented in the resolution score (excitement and depression), indicating that the resolution score is mainly representative for the core symptoms and less for non-diagnostic symptoms of schizophrenia (Van Os et al., 2006). Third, using threshold criteria such as resolution allows to better study the effect on the core symptoms and comorbid symptoms separately. 20%, 30% or even 50% reduction is an arbitrary outcome definition: it depends on PANSS baseline, is not correlated with outcome in daily functioning and it describes a heterogeneous group of patients. Response rates increase over time as is the % of patients in resolution. However the % of patients in resolution is consistently lower since it is a more severe criterion: about 50% of responders do not achieve resolution within 6 weeks, 3% achieves resolution without 20% improvement and 1 patient was clinically diagnosed with an acute exacerbation while achieving the resolution criteria. This indicates that resolution and
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J. Peuskens et al. / Schizophrenia Research 95 (2007) 169–173
20% improvement are not measuring the same: Resolution is a threshold score and is a more robust and clinically meaningful outcome parameter compared to 20% improvement. A drug will be considered as efficacious in fewer patients. Another advantage of the use of resolution criteria is that the core symptoms of schizophrenia are evaluated: 20% reduction on the PANSS could mean that the patient is sedated, less anxious or depressed, but still very psychotic, disorganised or with severe negative symptoms. As such we propose to use the resolution criteria as an outcome in clinical trials of acute psychosis. Absolute thresholds reliably evaluated for instance with PANNS facilitate clinical interpretation and efficacy comparisons between trials and treatments. Within a week of treatment 5.6% of the patients achieved resolution and of those in resolution at week two, 85% (47/55) remained so at week 6, indicating that onset of antipsychotic action can be fast and robust (Kapur et al., 2005). Patients who achieve resolution show the largest symptom reduction during the first 3 weeks and continue to improve. Overall, patients not achieving resolution at week 6 were slow and poor responders in the first 4 weeks. It could be considered to switch these patients to another treatment because of possible interpatient variability in drug response. None of the 18.3% drop outs discontinued treatment while in resolution. Lack of disease insight and side effects are common reasons for patients to discontinue their treatment. These data also show that robust clinical improvement can motivate patients to continue treatment. In the CATIE study (Lieberman et al., 2005), most patients discontinued their initial treatment because of inefficacy (23%) compared to intolerability (15%). Also psychiatrists switched more patients to a different treatment because of inefficacy (20%, n = 283) and only 11% (n = 168) because of intolerability (McEvoy et al., 2006; Stroup et al., 2006). In conclusion: Resolution seems to be an achievable, easy, useful and clinically meaningful outcome measure for use in clinical trials of acute psychosis. Role of the funding source The open-label study was funded, designed and followed up by Eli Lilly Belgium. Contributors Joseph Peuskens designed the supplementary, exploratory analysis plan, Betty Van Vleymen managed literature searches and wrote the first draft and Leonard Kaufman undertook the statistical analysis. All authors contributed to the interpretation of the analyses and have approved the final manuscript.
Conflict of interest Joseph Peuskens received consultancy fees from Eli Lilly for various projects, Betty Van Vleymen is an employee of Eli Lilly Belgium and Leonard Kaufman received an honorarium for the statistical analysis.
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