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CATIE and CUtLASS: can we handle the truth?

  • Shôn Lewis (a1) and Jeffrey Lieberman (a2)

Two large, non-commercial clinical trials comparing first- and second-generation antipsychotic drugs for people with chronic schizophrenia in the US and UK have shown unexpected results. In general, the newer drugs were no more effective or better tolerated than the older drugs. Clozapine outperformed other second-generation drugs. The implications are considered.

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Corresponding author
Professor Shôn Lewis, University of Manchester University Place (3rd floor east), Stopford Building, Oxford Road, Manchester M13 9PL, UK. Email:
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Declaration of interest

S. L. is the Chief Investigator of the CUtLASS study and J. L. is the Chief Investigator of the CATIE study. S. L. has received honoraria from several pharmaceutical companies. J. L. has received research funding from several pharmaceutical companies.

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8 Lieberman, JA, Stroup, S, McEvoy, JP, Swartz, MS, Rosenheck, RA, Perkins, DO, Keefe, RSE, Davis, SM, Davis, CE, Lebowitz, BD, Severe, J, Hsiao JK, for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353: 1209–23.
9 Keefe, RS, Bilder, RM, Davis, SM, Harvey, PD, Palmer, BW, Gold, JM, Meltzer, HY, Green, MF, Capuano, G, Stroup, TS, McEvoy, JP, Swartz, MS, Rosenheck, RA, Perkins, DO, Davis, CE, Hsiao, JK, Lieberman, JA, for the CATIE Investigators and the Neurocognitive Working Group. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial. Arch Gen Psychiatry 2007; 64: 633–47.
10 McEvoy, JP, Lieberman, JA, Stroup, TS, Davis, SM, Meltzer, HY, Rosenheck, RA, Swartz, MS, Perkins, DO, Keefe, RSE, Davis, CE, Severe, J, Hsiao JK, for the CATIE Investigators. 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 2006; 163: 600–10.
11 Jones, PB, Barnes, TR, Davies, L, Dunn, G, Lloyd, H, Hayhurst, KP, Murray, RM, Markwick, A, Lewis, SW. Randomized controlled trial of effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia. Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006; 63: 1079–87.
12 Lewis, SW, Barnes, TRE, Davies, L, Murray, RM, Dunn, G, Hayhurst, KP, Markwick, A, Lloyd, H, Jones, PB. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull 2006; 32: 715–23.
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14 Soares, BG, Fenton, F, Chue, P. Sulpiride for schizophrenia Cochrane Library, issue 3. Update Software, 2002.
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17 Rosenheck, RA, Leslie, D, Sindelar, J, Miller, EA, Lin, H, Stroup, TS, McEvoy, J, Davis, SM, Keefe, RSE, Swartz, MS, Perkins, DO, Hsiao, JK, Lieberman J, for the CATIE Study Investigators. Cost-effectiveness of second generation antipsychotics and perphenazine in a randomized trial of treatment for chronic schizophrenia. Am J Psychiatry 2006; 163: 2080–9.
18 Davies, LM, Lewis, S, Jones, PB, Barnes, TRE, Gaughran, F, Hayhurst, K, Markwick, A, Lloyd H on behalf of the CUtLASS team. Cost-effectiveness of first-v. second-generation antipsychotic drugs: results from a randomised controlled trial in schizophrenia responding poorly to previous therapy. Br J Psychiatry 2007; 191: 1422.
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CATIE and CUtLASS: can we handle the truth?

  • Shôn Lewis (a1) and Jeffrey Lieberman (a2)
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Handling the Truth?

Richard E Hodgson, Psychiatrist
18 June 2008

Dear Sir

Lewis and Lieberman (1) highlight the dilemma of evidence based prescribing in their provocatively titled editorial. In order to handle the truth it must first be established. Given the large number of trials comparing antipsychotics it is unlikely that the truth will emerge by focusing on two studies. Whilst the CATIE methodology may reflect a more pragmatic facsimile of real world prescribing it is, nonetheless, a randomised controlled trial (RCT) (with attendant high drop out rates), as is CUtLASS. Therefore, it is erroneous to claim that either study is a realistic measure of effectiveness (“as really used in clinical practice”). Recently Khan and colleagues (2) published the results of EUFEST an open label RCT of atypicals against low dose haloperidol with a primary endpoint of treatment discontinuation in first episode schizophrenia patients. 61% of patients on haloperidol discontinued treatment. This discontinuation rate was significantly higher than for thefour atypical antipsychotics included in the trial. Another non commercial sponsored open label RCT (3) used a pragmatic end point of discharge rate in which higher dose haloperidol performed as well as two atypicals and better than two other atypicals. However, more traditional rating scale end points revealed no difference between the various drugs which may suggest that clinicians and patients are more sensitive to factors between agents in clinical practice that are not apparent using current outcome scales. A similar effect was seen in EUFEST. It may also be that differences may become noticeable in studies if other outcomes areused. For example, attenuation of the reduction in brain volume associatedwith schizophrenia has been demonstrated with olanzapine but not haloperidol (4).

The largest, non-commercially sponsored study of effectiveness (5) revealed significant differences between antipsychotics both atypical and typical in 2230 first episode patients with schizophrenia followed up for up to seven years with clinically relevant such as treatment discontinuation and hospitalisation. The use of propensity scoring controlled for non-randomisation effects. The only consistent finding between CATIE, CUtLASS and Tiihonen et al (5) was the superiority of clozapine (refs 2 and 3 did not study clozapine). Apart from CUtLASS all the studies show differences between both typical and atypical antipsychotics. In practice little is known about prescribing decisions but these decisions are likely to be a function of personal experience as well as the published evidence base. Therefore, the truth for clinicians is not so obvious and what is needed is a review of how clinical trials are conducted so that the strengths of observational studies and RCTs can be combined to provide better information for practicing clinicians and their patients.

1.Lewis S, Lieberman J. CATIE and CUtLASS can we handle the truth? Br J Psychiatry 2008; 192: 161-163.

2.Kahn RS, Fleischhacker WW, Boter H et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. 2008 Lancet; 371: 1085-1097.

3.McCue RE, Waheed R, Urcuyo G et al Comparative effectiveness of second generation antipsychotics and haloperidol in acute schizophrenia. Br J of Psychiatry. 2006; 189: 433-440.

4.Lieberman, JA, Tollefson, GD, Charles, C et al Antipsychotic DrugEffects on Brain Morphology in First-Episode Psychosis. Arch Gen Psychiatry. 2005; 62:361-370.

5.Tiihonen J, Walhbeck K, Lönnqvist J, et al. Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study. 2006; BMJ, 333: 224.
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Conflict of interest: None Declared

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The truth about sulpiride?

Philip J Cowen, Professor of Psychopharmacology
09 April 2008

I congratulate Shôn Lewis and Jeffrey Lieberman on their editorial “CATIE and CUtLASS: can we handle the truth?” (1) Their pragmatic studies exemplify the kind of clinical trials we need to inform our practice, and all the clinicians and researchers involved deserve our gratitude. A question remains, though: can Shôn handle the truth about sulpiride?

Sulpiride and the “atypical” antipsychotic, amisulpiride, are both substituted benzamides. They have similar structures (2) and pharmacological profiles (3). The “recent” Cochrane review that Shôn cites(latest substantive amendment in 1998)(4) concludes that the poor quality of the trials (the past is another country) makes it impossible to draw firm conclusions about how sulpiride stands clinically in relation to typical antipsychotic drugs.

The authors of the review note, however, that “the incidence of side effects may be less for sulpiride” and add, “For those making economic andpolicy decisions there seems no reason to forget sulpiride as a useful antipsychotic that may cause less side effects than the typical antipsychotics and has never been compared to the increasingly dominant atypical drugs that are more expensive.”

CUtLASS has certainly remedied the latter omission but the experienced clinicians who carried out the study seem to have got there first!

1.Lewis S, Lieberman J. CATIE and CUtLASS: can we handle the truth? Br J Psychiatry 2008; 192: 161-163.2.Lidow MS. Neurotransmitter receptors in actions of antipsychotic medications. CRC Press, 2000, pp20.3.Roth BI, Sheffler D, Potkin SG. Atypical antipsychotic drug actions: unitary or multiple mechanisms for atypicality? Clin Neurosci Res 2003; 3: 108-117. 4.Soares BGO, Fenton M, Chue P. Sulpiride for schizophrenia. Cochrane Database of Systematic Reviews 1999; Issue 1: Art. No.: CD001162. DOI: 10.1002/14651858.CD001162.
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Conflict of interest: None Declared

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Some Issues with Cutlass

Mark Agius, Associate Specialist BLPT
17 March 2008

Lewis [1] asks us to handle the truth regarding the Cutlass I study [2]. However, close scrutiny of the study shows that, eventhough there is no doubt that the results of the study and its statisticalanalysis appear to be robust enough, the design of the study itself does not allow for any generalisation of the findings to a general statement regarding the cost utility of second and first generation anti-psychotic therapy outside of the study sample itself. Particular issues which arise include;The choice , as a starting point of the study , of patients requiring a change of medication , either by reason of efficacy or of side effects. This excludes, from any estimate of cost efficacy all patients whose firstantipsychotic treatment –often a second generation drug, -has proved appropriate and effective.The fact that , since over 40% of patients in the First Generation anti-psychotic group were put on Sulpride, these patients represent a most unusual group, since Sulpride is a drug among the first generation group which has some unusual properties compared to the rest of the group, making it similar to amisulpride, which is considered to be within the second generation group[3] .The question as to whether the terms First Generation and Second Generation groups of anti-psychotics are at all meaningful , given the heterogeneity in terms of pharmaceutical properties of the antipsychotics within each group; Indeed , does Typicality and Atypicality have the same meaning as First or Second Generation?The issue of anti-psychotic combination treatment, which suggests the presence in this study of particularly difficult to treat patients.The fact that, within the first generation group, some patients were put on depot injectable preparations while others were put on oral medications. In the second generation group, all patients were put on oralmedication, so there were differences in compliance issues and how they could be expressed by patients in the two groups.The difficulty , given that the only total readings on the Quality of Lifescale are presented and compared in the findings, of being clear what precise improvement of ‘Quality of Life’ occurred in the First and Secondgeneration group.

The lack of reporting, during the study, of any other interventions ,such as Cognitive Therapy or Assertive Case Management which could haveimpacted on the quality of life of some study patients more than on others.All of these factors taken together suggest that the conclusion that thereis no difference in cost efficacy between first and second generation medications must remain a matter for further exploration despite the findings of this study.In particular it seems unwise to use the CuTLASS data as a reason for not using atypical antipsychotics in patients with first and early episodes ofpsychotic illness.[4,5]

[1] Lewis S, Lieberman J 2008 CATIE and Cutlass can we handle the truth? Br J Psychiatry 192; 161-163.[2] Jones PB, Barnes TRE, Davies L, Dunn G , Lloyd H, Hayhurst KP, Murray RM, Markwick A, Lewis SW 2006 Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 63; 1079-1087[3] Bazire S Psychotropic Drug Directory 2005 p126[4] IRIS Guidelines North Birmingham Mental Health Trust 1999[5] NICE Guidelines on Schizophrenia 2002
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