Is a combined therapy more effective than either CBT or SSRI alone? Results of a multicenter trial on panic disorder with or without agoraphobia
van Apeldoorn FJ, van Hout WJ, Mersch PP, Huisman M, Slaap BR, Hale WW 3rd, et al.;
Commented by , 31 Jan 2008
Aim of study
To determine whether combined therapy with a selective serotonin reuptake inhibitor (SSRI) and cognitive behaviour therapy (CBT) was superior to either treatment modality alone.
Patients with DSM-IV panic disorder with or without agoraphobia were randomly allocated to one of three arms: SSRI, CBT, or SSRI + CBT in this multi-centre trial conducted in the Netherlands. Centres included university training clinics and non-academic mental health clinics.
Outcome measures were obtained at 9 months. There were two categorical measures.
First, responders: defined by meeting predetermined criteria in at least three of the Patient Global Evaluation Improvement (PGE-I), Patient Global Evaluation Improvement (PGE-S), Clinical Global Impression Improvement (CGI-I) and Clinical Global Impression Severity (CGI-S).
Second, panic free: no panic attacks for a 2 week period after 9 months. Continuous measures included the Hamilton Anxiety Inventory (HAM-A), Agoraphobia subscale of the Fear Questionnaire (FQ-AG), Beck Depression Inventory (BDI) and the Symptoms Checklist (SC-90).
The primary outcome was whether SSRI + CBT produced a favourable outcome at nine months compared with either alone. A comparison was also made between the SSRI and CBT groups.
The SSRI + CBT group was superior to the CBT alone group in all outcome measures. There were no significant differences between the SSRI + CBT group verses the SSRI alone group on an intention to treat analysis. The SSRI group proved superior to the CBT group on four measures.
Dr Christmas', Dr Hood's and Prof Nutt's comments
Both CBT and SSRIs have proven efficacy in the treatment of panic disorder. Due to their radically different mechanisms of action the notion that a combination of both treatments will be superior to either alone has significant face validity. To date, this is not supported by robust evidence (ref. 1, ref. 2).
In public health settings the lack of availability of CBT often necessitates treatment with an SSRI in the first instance, with CBT a second line intervention. This clinical practice is supported by this paper - SSRIs alone will perform as well as SSRIs + CBT and may perform better than CBT alone. Thus, step-wise treatment algorithms such as those advocated by the British National Institute of Clinical Excellence (NICE) (ref. 3) are both pragmatic and supported by the evidence.
There are a few methodological concerns that remain unaddressed by this paper. First, the authors found no difference between efficacy of CBT provided by the different centres (academic specialist verses "standard" mental health) and cite this as evidence that CBT can effectively be reproduced outside of "expert" centres. (A criticism oft levelled at the evidence base of CBT is that it is delivered in expert settings that may not be reproducible in routine mental health services).
However, there was a difference in expertise between the treatment centres; the "expert" centres used trainees with close supervision whereras the "standard" teams used experienced therapists. Neither of these may give the same efficacy as is seen in other trials where experienced therapists in expert centres provide the CBT.
This problem is compounded by the second methodological issue; viz the lack of any placebo controls. The authors cite the good evidence for both SSRIs and CBT in panic disorder as a reason not to have any placebo controls in this study. However, this then distorts any comparison with the existing evidence base.
A parsimonious alternative explanation for the results here is that results overall were inflated by a large placebo response (explaining the better than expected effect sizes of SSRI and SSRI + CBT groups), but that the CBT provided in the study was no better than placebo.
It has already been discussed in April 2007 on this forum [click on this link to see article] the need for good placebo controls of CBT trials, with examples of good trials already in the literature (ref. 4). Therefore this paper does not inform us whether CBT is equally efficacious when provided in naturalistic settings compared to expert ones.
This study also brings back into focus another issue discussed in this forum in April 2007; the need to determine which patients will respond best to CBT. With "blunderbuss" augmentation of SSRI treatment performing no better than SSRI treatment alone, this is especially important for public health services with scarce resources.
The targeting of CBT to those with most to benefit from it may well provide not only a more cost effective solution, but also provide further insights into the heterogeneity of panic disorder.
1. van Balkom AJ, Bakker A, Spinhoven P, Blaauw BM, Smeenk S, Ruesink B. A meta-analysis of the treatment of panic disorder with or without agoraphobia: a comparison of psychopharmacological, cognitive-behavioral, and combination treatments. Journal of Nerveous and Mental Disease 1997; 185 (8); 510-516
2. Barlow DH, Gorman JM, Shear MK, Woods SW. Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: A randomized controlled trial. JAMA 2000; 283 (19); 2529-2536
3. Barlow DH, Gorman JM, Shear MK, Woods SW. Clinical Guidelines for the Management of Anxiety Management of anxiety (panic disorder, with or without agoraphobia, and generalised anxiety disorder) in adults in primary, secondary and community care. NICE 2004; [CG22]; 1-165
4. Heimberg RG, Liebowitz MR, Hope DA, Schneier FR, Holt CS, Welkowitz LA, et al. Cognitive behavioral group therapy vs phenelzine therapy for social phobia: 12-week outcome. Archives of General Psychiatry 1998; 55 (12); 1133-1141