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1814 www.thelancet.com Vol 381 May 25, 2013

blind does not preclude the inclusion of a credible control.

If a paper were submitted to The Lancet in which a drug had been evaluated as described above, it would have been mercilessly rejected, the reviewers harshly pointing out that a comparison with standard care permits no conclusion whatsoever regarding true effi cacy. But for studies of cognitive behavioural therapy (CBT), the journal applies very diff erent standards, as shown by the publication of the report by Nicola Wiles and colleagues (Feb 2, p 375),2 as well as other papers.3–5

Why is a design precluding conclusions less of a problem for CBT trials than for drug trials?I declare that I have no confl icts of interest.

Elias Erikssonelias.eriksson@neuro.gu.se

University of Gothenburg, Institute of Neuroscience and Physiology, Department of Pharmacology, Gothenburg S40530, Sweden

1 Landén M, Björling G, Agren H, Fahlén T. A randomized, double-blind, placebo-controlled trial of buspirone in combination with an SSRI in patients with treatment-refractory depression. J Clin Psychiatry 1998; 59: 664–68.

2 Wiles N, Thomas L, Abel A, et al. Cognitive behavioural therapy as an adjunct to pharmacotherapy for primary care based patients with treatment resistant depression: results of the CoBalT randomised controlled trial. Lancet 2013; 381: 375–84.

3 Otto MW, Wisniewski SR. CBT for treatment resistant depression. Lancet 2013; 381: 352–53.

4 Nijhof SL, Bleijenberg G, Uiterwaal CS, Kimpen JL, van de Putte EM. Eff ectiveness of internet-based cognitive behavioural treatment for adolescents with chronic fatigue syndrome (FITNET): a randomised controlled trial. Lancet 2012; 379: 1412–18.

5 Kessler D, Lewis G, Kaur S, et al. Therapist-delivered Internet psychotherapy for depression in primary care: a randomised controlled trial. Lancet 2009; 374: 628–34.

1 Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet 2013; 381: 29–39.

2 Blair JE, Khan S, Konstam MA, et al. Weight changes after hospitalization for worsening heart failure and subsequent re-hospitalization and mortality in the EVEREST trial. Eur Heart J 2009; 30: 1666–73.

3 Gheorghiade M, Vaduganathan M, Fonarow GC, Bonow RO. Rehospitalization for heart failure: problems and perspectives. J Am Coll Cardiol 2013; 61: 391–403.

4 Felker GM, Benza RL, Chandler AB, et al. Heart failure etiology and response to milrinone in decompensated heart failure: results from the OPTIME-CHF study. J Am Coll Cardiol 2003; 41: 997–1003.

5 Metra M, Cotter G, Davison BA, et al. Eff ect of serelaxin on cardiac, renal, and hepatic biomarkers in the relaxin in acute heart failure (RELAX-AHF) development program: correlation with outcomes. J Am Coll Cardiol 2013; 61: 196–206.

patients had 3 kg bodyweight loss at day 14 (only 0·6 kg less than patients receiving placebo). We are committed to understanding serelaxin’s eff ects on rehospitalisation, beyond the confounding eff ects of the greater proportion of patients with a history of previous hospitalisation for heart failure, the shorter length of stay and the improved survival in the serelaxin-treated patients. Short-term rehospitalisations might also be more related to non-modifi able factors (eg, social support, geographic location, and socioeconomics) so that there is a disconnect between early readmissions and post-discharge mortality.3

The RELAX-AHF trial reported a 37% reduction in mortality, but it was not prospectively powered to assess mortality, so the concept of the study power for this endpoint is problematic. The ability of a short-term infusion to have long-term eff ect on outcomes has already been clearly shown in the area of thrombolytics, and AHF, for which short-term infusions of inotropes result in both early and late increases in mortality.4 AHF is a syndrome in which end organ damage occurs early and is related to subsequent mortality. We hypothesise that early treatment with serelaxin might prevent or reduce this end organ damage and might reduce mortality. Secondary analyses of RELAX-AHF provide additional support for this hypothesis,5 and a clinical trial with mortality as the prospectively defi ned primary endpoint is being planned.

Additional analyses are required to better understand the role of serelaxin in the treatment of patients with AHF. We have received consulting fees and clinical research grants from Corthera, a Novartis affi liated company (the sponsor of the RELAX-AHF trial).

*John R Teerlink, Marco Metra, on behalf of the RELAX-AHF investigatorsjohn.teerlink@ucsf.edu

San Francisco Veterans Aff airs Medical Center and School of Medicine, University of California San Francisco, San Francisco, CA, 94121-1545, USA (JRT); and University of Brescia, Brescia, Italy (MM)

Cognitive behavioural therapy for treatment- resistant depression

If a trial is designed with pill X added to ongoing drug treatment in depressed, non-responding patients, clear-cut improvement should be expected in those receiving X, rather than standard care, even if X is a placebo.1 If X is replaced by a psychotherapy Y, the outcome should be equally easy to predict. Undoubtedly, larger symptom reduction would be obtained in patients receiving this extra dose of attention, whatever its nature is.

This talk-induced improvement could be attributable to the non-specifi c support provided, or to the fact that patients meeting regularly with a kind therapist might fi nd it impolite to deny any improvement. Also, being regularly reminded of the nature of their disorder might increase patients’ adherence to their medication.

To claim that Y, in addition to such non-specifi c factors, exerts a specifi c eff ect, one would have to show superiority versus some other treatment. The fact that psychotherapy studies are diffi cult to

Authors’ replyElias Eriksson raises the question of the need for an attention control in trials of psychological interventions. We can provide some background to this question with regards to our recent publication of the CoBalT trial.1

As outlined in our paper, we asked a pragmatic question about the value of addition of psychological therapy (specifi cally, cognitive behavioural

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the rest had no known contact with poultry.

Unlike in Shanghai where there might have been a common source of outbreak from the market, the sequential reports of H7N9 infections in the rest of the country suggest transmissions of the viruses over a large area spanning several cities and provinces (appendix).

In view of the importance of the poultry population (billions of animals), and the numbers of farms, the virus could continue to spread. There is a need to control poultry at farm level, possibly through massive poultry vaccination, and urban out-breaks could be halted by banning imports or central slaughtering.We declare that we have no confl icts of interest.

*Shui Shan Lee, Ngai Sze Wong, Chi Chiu Leungsslee@cuhk.edu.hk

Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, China (SSL, NSW); and Tuberculosis and Chest Service, Department of Health, Hong Kong, China (CCL)

1 Chen Y, Liang W, Yang S, et al. Human infections with the emerging avian infl uenza A H7N9 virus from wet market poultry: clinical analysis and characterisation of viral genome. Lancet 2013; published online April 25. http://dx.doi.org/10.1016/S0140-6736(13)60903-4.

2 Gao R, Cao B, Hu Y, et al. Human infection with a novel avian-origin infl uenza A (H7N9) virus. N Engl J Med 2013; published online April 11.DOI:10.1056/NEJMoa1304459.

3 Shi J, Deng G, Liu P, et al. Isolation and characterization of H7N9 viruses from live poultry markets – implication of the sources of current H7N9 infection in humans. Chi Sci Bull 2013; DOI:10.1007/s11434-013-5873-4.

4 Li Q, Zhou L, Zhou M, et al. Preliminary Report: epidemiology of the avian infl uenza A (H7N9) outbreak in China. N Engl J Med 2013; published online April 24. DOI:10.1056/NEJMoa1304617.

coauthored a cognitive therapy book (Collaborative Case Conceptualization, Guilford Press). The other authors declare that they have no confl icts of interest.

*Nicola Wiles, Glyn Lewis, Tim Peters, Willem Kuyken, Chris Williams nicola.wiles@bristol.ac.uk

Centre for Mental Health, Addiction and Suicide Research, School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK (NW, GL), School of Clinical Sciences, University of Bristol, Bristol, UK (TP), Mood Disorders Centre, University of Exeter, Exeter, UK (WK); and Academic Unit of Mental Health and Wellbeing, Institute of Health and Wellbeing, University of Glasgow, Gartnavel Royal Hospital, Glasgow, UK (CW)

1 Wiles N, Thomas L, Abel A, et al. Cognitive behavioural therapy as an adjunct to pharmacotherapy for primary care based patients with treatment resistant depression: results of the CoBalT randomised controlled trial. Lancet 2013; 381: 375–84.

2 Roth AD, Pilling S. The competencies required to deliver eff ective cognitive and behavioural therapy for people with depression and with anxiety disorders. London: Improving Access to Psychological Therapies (IAPT) programme, Department of Health; 2007.

3 Bower P, Knowles S, Coventry PA, Rowland N. Counselling for mental health and psychosocial problems in primary care. Cochrane Database Syst Rev 2011; 9: CD001025.

therapy [CBT]) to usual care (that included continued pharmacotherapy) as a next step treatment for patients whose depression had not responded to treatment with antidepressant medication alone. Hence, an attention control was regarded as of little value because such an intervention would be unlikely to be implemented within the National Health Service. In an ideal world, such trials would have two comparator groups—usual care and an attention control. However, such a design would be much more expensive, potentially more problematic to recruit to, and the inclusion of an attention control might raise ethical issues particularly with a vulnerable population, such as the population recruited in CoBalT.

In trials of medication, the non-specifi c aspects of treatment that are studied using a placebo have little interest to the pharmacologist, doctor, or patient. By contrast, it is recognised that all psychotherapies, including CBT, have non-specifi c eff ects that are shared by all psychological treatments and need to be identifi ed and encouraged.2 It is possible that some (or even all) of the treatment eff ect we recorded could be explained by such factors that are not specifi c to CBT. However, an independent evaluation confi rmed that fi delity to the CBT model was good,1 and other investigators have done studies that inform this point. For example, there is little evidence that counselling is eff ective for mental health problems in the long-term.3 By contrast, we report that the improvements in depression and secondary outcomes, such as quality of life, were maintained at 12 months, clearly showing the longer-term eff ectiveness of CBT given as an adjunct to pharmacotherapy in patients with treatment resistant depression. CW has been a past president of the British Association for Behavioural and Cognitive Psychotherapies (BABCP), a workshop leader, and author of texts on depression and self-help resources. WK is cofounder of the Mood Disorders Centre, teaches nationally and internationally on CBT and

Exposure to avian infl uenza H7N9 in farms and wet markets

In two studies describing clinico-epidemiological characteristics of H7N9-infected patients in China, 6 out of 7 patients had a history of exposure to market poultry.1,2 In Shanghai and Anhui, 20 of 280 specimens isolated from live market poultry were positive for H7N9, while none of 690 specimens isolated from farm poultry were positive.3 58% (34/59) of H7N9-infected patients had a history of visiting poultry markets.4 Although the importance of exposure to market poultry is acknowledged, exposure to farm poultry is a cause for concern, especially in rural China.

We re-examined all media–reported cases from offi cial sources as of April 29, 2013. Of 125 cases, 25 (20%) were associated with farm exposure, 12 (10%) with market exposure, and

Published OnlineMay 10, 2013http://dx.doi.org/10.1016/S0140-6736(13)60949-6

See Online for appendix

Reducing exposure to avian infl uenza H7N9Avian infl uenza H7N9 infections have extended to 39 cities in 10 provinces, infected 127 patients and killed 26 people in China as of May 1, 2013.1 This outbreak is very diffi cult to control, and covers a greater geographical area than thought.2 Stopping infection of people in China is a huge challenge.

Published OnlineMay 10, 2013http://dx.doi.org/10.1016/S0140-6736(13)60950-2