Efficacy and Acceptability of Pharmacological Treatments for Depressive Disorders in Primary Care: Systematic Review and Network Meta-Analysis

Klaus Linde; Levente Kriston; Gerta Rücker; Susanne Jamil; Isabelle Schumann; Karin Meissner; Kirsten Sigterman; Antonius Schneider

doi:10.1370/afm.1687

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Author reply to the letter by Hegerl and Mergl
Klaus Linde

Published on: 05 February 2015
Remarks to "Efficacy and Acceptability of Pharmacological Treatments for Depressive Disorders in Primary Care: Systematic Review and Network Meta-Analysis" by Klaus Linde et al. and "Treatment of Depression in Primary Care" by Frank deGruy
Ulrich Hegerl

Published on: 27 January 2015

Published on: (5 February 2015)
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Author reply to the letter by Hegerl and Mergl
Klaus Linde, Research Coordinator
Other Contributors:
We thank Hegerl and Mergl for their thoughtful comments [1]. They ask to "take care not to underestimate the benefits of antidepressants and overestimate those of psychotherapy." Indeed, the findings of our two meta-analyses [2,3] must be interpreted with great caution when it comes to the question which of the two basic options is more effective. As emphasized in our papers, trials on drug treatments and psychological tr...
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We thank Hegerl and Mergl for their thoughtful comments [1]. They ask to "take care not to underestimate the benefits of antidepressants and overestimate those of psychotherapy." Indeed, the findings of our two meta-analyses [2,3] must be interpreted with great caution when it comes to the question which of the two basic options is more effective. As emphasized in our papers, trials on drug treatments and psychological treatments differ in many important aspects. One such aspect mentioned by Hegerl and Mergl is the use of different control groups (placebo vs. usual care). However, real waitlist controls were rarely used in our trial set and usual care, while insufficiently described in most publications, often was more than watchful waiting. Only few trials have directly compared antidepressants and psychological treatments in a primary care setting (the trial by Hegerl et al. [4] was excluded from our reviews, because none of the studied treatments was provided in a primary care practice). The findings of these direct comparisons as well as of mixed direct and indirect comparisons using network-meta-analysis have not been addressed in our papers but will be covered by upcoming manuscripts.
Hegerl and Mergl argue that the use of intention-to-treat (ITT) analysis and the lack of flexibility in drug trials underestimate the benefit in compliant patients tolerating drug treatment in routine practice. This might be true to some extent. However, the use of ITT analysis is generally preferred to per protocol analysis as the latter runs the risk of mixing the treatment effect with selection effects and variations in compliance [5]. Furthermore, about half of the trials included in our analysis allowed some flexibility in dosing with some even permitting medication change. Our method of treating patients with missing data in all study arms as non-responders should not be equated with a last observation carried forward approach, but this is unlikely to make a substantial difference. In addition to our primary analysis, we performed a secondary analysis (not presented in our publication [2,3]) based on what the study authors presented as primary findings (which was a mix of ITT, available cases and per-protocol data). In this analysis, the estimated effects over placebo were slightly larger (e.g. point estimates for SSRI were 1.83 compared to 1.75 in our primary analyses, for tricyclic antidepressants 1.81 vs. 1.67).
In the end what is needed are large pragmatic randomized trials comparing realistic treatment options under conditions close to routine care over longer periods as well as naturalistic, well-documented cohorts to check external validity of trial findings. And clearly, the documentation of adverse events under psychological therapy has to be improved.
1. Hegerl U, Mergl R. Remarks to "Efficacy and Acceptability of Pharmacological Treatments for Depressive Disorders in Primary Care: Systematic Review and Network Meta-Analysis" by Klaus Linde et al. and "Treatment of Depression in Primary Care" by Frank deGruy [eletter]. Ann Fam Med. http://www.annfammed.org/content/13/1/69/reply#annalsfm_el_28862, 27 January 2105.
2. Linde K, Kriston L, Ruecker G, Jamil S, Schumann I, Meissner K, Sigterman K, Schneider A. Efficacy and acceptability of pharmacological treatments for depressive disorders in primary care: Systematic review and network meta-analysis. Ann Fam Med. 2015;13:69-79.
3. Linde K, Sigterman K, Kriston L, Ruecker G, Jamil S, Meissner K, Schneider A. Effectiveness of psychological treatments for depressive disorders in primary care: systematic review and meta-analysis. Ann Fam Med. 2015;13:56-68.
4. Hegerl U, Hautzinger M, Mergl R, Kohnen R, Schuetze M, Scheunemann W, Allgaier AK, Coyne J, Henkel V. Effects of pharmaco- and psychotherapy in depressed primary care patients. A randomized, controlled trial including a patient choice arm. Int J Neuropsychopharmacol. 2010;13:31-44.
5. Detry MA, Lewis RJ. The intention-to-treat principle: how to assess the true effect of choosing a medical treatment. JAMA. 2014;312:85-86.
Competing interests: None declared
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Competing Interests: None declared.
Published on: (27 January 2015)
Page navigation anchor for Remarks to "Efficacy and Acceptability of Pharmacological Treatments for Depressive Disorders in Primary Care: Systematic Review and Network Meta-Analysis" by Klaus Linde et al. and "Treatment of Depression in Primary Care" by Frank deGruy
Remarks to "Efficacy and Acceptability of Pharmacological Treatments for Depressive Disorders in Primary Care: Systematic Review and Network Meta-Analysis" by Klaus Linde et al. and "Treatment of Depression in Primary Care" by Frank deGruy
Ulrich Hegerl, Director
Other Contributors:
Remarks to "Efficacy and Acceptability of Pharmacological Treatments for Depressive Disorders in Primary Care: Systematic Review and Network Meta-Analysis" by Klaus Linde et al. and "Treatment of Depression in Primary Care" by Frank deGruy
Ulrich Hegerl*[1] and Roland Mergl[1]
[1] Department of Psychiatry and Psychotherapy, University of Leipzig, Semmelweisstr. 10, D-04103 Leipzig, Germany
Addres...
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Remarks to "Efficacy and Acceptability of Pharmacological Treatments for Depressive Disorders in Primary Care: Systematic Review and Network Meta-Analysis" by Klaus Linde et al. and "Treatment of Depression in Primary Care" by Frank deGruy
Ulrich Hegerl*[1] and Roland Mergl[1]
[1] Department of Psychiatry and Psychotherapy, University of Leipzig, Semmelweisstr. 10, D-04103 Leipzig, Germany
Address of correspondence:
* Professor Dr. med. Ulrich Hegerl; Department of Psychiatry and Psychotherapy, University of Leipzig, Semmelweisstr. 10, D-04103 Leipzig, Germany; Semmelweisstr. 10; D-04103 Leipzig, Germany; phone: 0341 9724530; fax: 0341 9724539; e-mail address: Ulrich.Hegerl@medizin.uni-leipzig.de.
In his methodologically sound meta-analysis regarding randomized clinical trials (RCT) in primary care, Linde et al. (1) found antidepressants to have significant but compared to placebo small antidepressant effects. DeGruy (2) discussed these findings putting them also in the context of psychotherapy as an alternative.
I would like to add two aspects to this discussion.
1) In daily practice the primary care provider sitting in front of a patient with milder forms of depression has often to decide between antidepressant treatment versus unspecific support (watchful waiting). Will the antidepressant have a clinically significant effect? Clinical significance is often estimated by looking how far patients randomized to the antidepressant do better than those receiving placebo. This approach, however, risks being grossly misleading. One of several reasons for that is the method of intention-to-treat analyses with last observation carried forward which Linde et al. (1) have chosen for their meta-analysis. This approach is useful to prove efficacy of antidepressants but will obviously underestimate the benefit a compliant patient who tolerates the drug can expect in daily practice (3). In routine care, but not within RCTs, medication is individually adapted in case of side effects (e.g. switching to another drug, changing dosages) or nonresponse (e.g. combination and augmentation strategies).
2) Sometimes the choice is between pharmaco- and psychotherapy. When comparing the effect size of these treatments, the fundamental problem should be mentioned that psychotherapy control conditions are not placebos ("I will please") but risk being nocebos. The patients cannot be blinded and are fully aware of being "in the control group only". This is likely to trigger frustration and despair. In our own study on primary care patients with depression (for unknown reasons not included in the meta-analysis by Linde et al. (1)) the psychotherapy control condition (psychoeducation, self-help activities) did significantly worse than CBT, sertraline and even pill placebo (4). The lack of placebo effect in psychotherapy control conditions inflates the effect sizes and this not only for waiting control groups. Concerns with regard to risks and side effects are generally larger for pharmaco- than psychotherapy and influence decision making. However, for psychotherapy systematic research on this topic, e.g. concerning a possible risk of suicide induction by psychotherapy, is lacking.
In summary while both pharmaco- and psychotherapy are valuable treatments for depressed patients in primary care, we should take care not to underestimate the benefits of antidepressants and overestimate those of psychotherapy.
References
(1) K. Linde, L. Kriston, G. Rucker, S. Jamil, I. Schumann, K. Meissner, K. Sigterman & A. Schneider. Efficacy and acceptability of pharmacological treatments for depressive disorders in primary care: Systematic review and network meta-analysis. Ann Fam Med. 2015;13:69-79.
(2) F.V. de Gruy. Treatment of depression in primary care. Ann Fam Med. 2015;13:3-5.
(3) M. Adli & U. Hegerl. Do we underestimate the benefits of antidepressants? Lancet. 2014;383:1361-1362.
(4) U. Hegerl, M. Hautzinger, R. Mergl, R. Kohnen, M. Schutze, W. Scheunemann, A.-K. Allgaier, J. Coyne & V. Henkel. Effects of pharmaco- and psychotherapy in depressed primary care patients. A randomized, controlled trial including a patient choice arm. IJNP. 2010;13:31-44.
Competing interests: Professor Hegerl has served as an advisory board member for Eli Lilly, Lundbeck, Otsuka, Takeda, and Servier, as a consultant for Nycomed, and as a speaker for Bristol-Myers Squibb, Medice Arzneimittel, Novartis, and Roche Pharma. Dr. Mergl has served as a consultant for Nycomed.
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Competing Interests: None declared.