Treatment For Depression: Does it Work? Does it Matter?

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Psychiatric treatment works to a degree comparable to other branches of medicine which address complex, chronic illnesses.

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AFFIRMING PSYCHIATRY

In a previous installment of this column, I took journalists to task for ignoring the revolutionary scientific confirmation that psychotherapy works. Talk therapy is indeed a scientifically legitimated and validated medical treatment on par with any other. Psychotherapy works for individuals of all age groups, and it works for those with every type of major mental illness. All of this is part of the larger story: Psychiatric treatment works. Medications work, electroconvulsive therapy works, transcranial magnetic stimualtion works, exercise works, and psychoeducation works, along with several other validated interventions. Psychiatric treatment works to a degree comparable to other branches of medicine which address complex, chronic illnesses.1

Of course, this is not the end of the discussion. While psychiatry’s treatments are proven to work, more sophisticated critics both inside and outside our field maintain that it just does not matter. Instead, they insist that most psychiatric treatments are minimally effective, so much so that they may not make much of a difference. Kirsch, for instance, has published widely-discussed meta-analyses of antidepressants showing relatively low effect sizes, and interpreted them as indications that “benefits of antidepressants seem to be minimal and possibly without any importance to the average patient.”2 The press has seized on such reports, although it has typically lost interest in the research-based discussions that have followed.3 Likewise, critical reviewers have noted that psychotherapy for depression fares little better than medications in trials which include strong placebo control groups.4

In the following paragraphs, I would like to discuss the question of whether psychiatry’s treatments make a meaningful difference. Because this is a complex and far-reaching question, I will focus on the most controversial area of all: major depressive disorder (MDD). Antidepressants are among the most commonly prescribed medications in all of medicine, while psychotherapy has been more thoroughly studied for depression than for any other medical condition. And yet in both cases critics maintain that these treatments barely distinguish themselves from placebo.

As the New York Times has put it, “Experts are divided over whether these small benefits make a noticeable difference to people’s moods or overall functioning.”5 One of those experts, Irving Kirsh, published a book under the subtly provocative title, The Emperor’s New Drugs: Exploding the Antidepressant Myth.6 Another well-publicized critic, Joanna Moncrieff, has asserted that antidepressants “produce no noticeable benefit compared with placebo.”7 Rather, she describes them as agents of emotional numbing comparable to alcohol, opiates, and benzodiazepines.8

As for the psychotherapy of depression, it looks neither better nor worse than medication in comparison to pill placebos. Thus, as prominent researchers Pim Cuijpers et al put it, “Whether these effects should be deemed clinically relevant remains open to debate.”9 Hardly a ringing endorsement, and Cuijpers’ ambivalence is magnified many times over in popular accounts such as, “Does Therapy Really Work? Let’s Unpack That,”4 and “Looking for Evidence That Therapy Works.”10 Let’s look at the question of how our treatments for depression stack up against placebo, and what that means for clinical practice.

A Word About Effect Sizes

“Effect size” is the most common medical measure of the success of a treatment. Measured in units of standard deviation compared to the control group, an effect size can be positive (superior to the control group), negative (inferior), or zero (identical to the control group). Effect sizes of 0.8 and above are considered high and reflective of a good medical treatment, while those of 0.2 or lower are considered mildly effective or weak treatments. In general, psychiatric treatments (primarily pharmacotherapy and psychotherapy) have an average effect size of 0.34-0.50.11 This represents an effect size on the lower end of moderate, but one that is in fact comparable to treatments in the rest of medicine for chronic conditions.1

In meta-analyses for treatments of depression, both psychotherapy and medications come out on the low side of this range, around 0.3-0.35.11 Worse still, it seems that most of the antidepressant effects that individuals experience in treatment are not due to the effects of antidepression medication. In fact, the placebo response seems to be about 80% of the response patients get with actual antidepressant medications.12 The same is likely to be true for studies of psychotherapy. This, then, is the basis of critics’ assertions that our treatments do not do much for patients with depression, even if they are proven treatments. Our treatments just do not do much more that placebo. Given their expense and risks, why use them at all?

What Is Placebo?

Fortunately for our patients, the critics are wrong. How can this be? In the first place, critics often lapse into the habit of acting like placebo is no treatment at all. The implicit idea is that placebo is an inert sugar pill which does nothing, and therefore our treatments do next to nothing. Yet it is well known that placebo pills in themselves are quite powerful, with effects noticed widely throughout medicine. The placebo improvement in mental health studies is far more than just the effect of a placebo pill.13 “Placebo” also includes a full psychiatric and medical evaluation, extensive laboratory work, and detailed psychoeducation about diagnosis and treatment options. More than that, patients in these studies receive more regular and extensive follow-up support than those typically treated for depression in the community.14 So patients who improve from placebo treatment get high quality general care in addition to the placebo pill. It is widely agreed that this is powerful treatment for MDD.

Placebo is, in fact, a complex set of treatments. Whereas patients in placebo groups show an average 38% response rate in studies, wait list controls in short term trials (4 to 12 weeks) show an average 12% response rate.15 When compared to wait list controls, both antidepressants and psychotherapy show high effect sizes. For instance, 1 meta-analysis showed that the effect size for psychotherapy as compared to wait list was 0.71 (a high effect size).16 Even Kirsch et al have calculated that patients who receive antidepressant medications in controlled studies experience an effect size of 1.24 compared to baseline, an “extremely large magnitude according to conventional standards.”17

My argument is not that wait list controls or comparison to baseline would be better standards. That is an issue for researchers. My point is that patients who receive psychiatric treatment in these studies improve a great deal. Psychiatric treatment for depression is hardly ineffective. The fact that the effects are the result of a complex mix of factors, including “placebo,” antidepressants, and psychotherapy does not make treatment any less effective. Antidepressant medications add additional benefit to general treatment, aka “placebo.” So does psychotherapy. As we know well, psychotherapy and medications together are more powerful than either alone. In fact, patients receiving combination treatment in studies improve by an effect size of 1.74 compared to baseline.18 What we see in studies is an accumulation of benefits acquired by patients who receive multiple interventions, including thorough psychiatric assessment, psychoeducation, general treatment support, antidepressants, and psychotherapy.

Research Versus the Real World

As a clinician, I would say that research on the treatment of MDD matches my experience quite well. In practice, different treatments for depression do not exist in isolated bubbles. Rather, they are and should be part of an integrated treatment experience. Most patients get significantly better, though remission usually is harder to attain and typically takes longer than the usual 6- to 12-week window of a typical research study. Treatment success seems to depend mostly on common factors in treatment more than the specifics of which treatment the patient and I select, but we can also squeeze additional benefit out of treatment by finding the right medication or form of psychotherapy. Monotherapy (eg, medication alone) can work, but multimodal therapy tends to work better.

When treatment does not work, we can often tip the balance by adding additional modalities, including exercise, mindfulness, social support, and intensive outpatient treatment. More importantly, treatment failure is usually a reminder to go back and reassess for complicating factors which would interfere with success. Substance use, anxiety, bipolarity, developmental trauma, poor sleep quality, and other undiagnosed medical conditions are common contributors. These are the very factors that exclude individuals for participation in studies in the first place, and they are the rule rather than the exception in most clinical practices.19 When there are resources to adequately address them, treatment success is likely.

Concluding Thoughts

Once again, we see that the loudest and harshest voices in the media are wrong about psychiatry. Once again, careful scientific study shows that psychiatric treatment works, and psychiatric treatment for depression works. Depression treatment works in a way comparable to treatments of other complex and chronic medical illnesses. Treatment of depression works with large effect sizes compared with no treatment at all.

Once again, good psychiatric treatment is relationally based, comprehensive, biopsychosocial treatment. The most important aspects of treatment are a good therapeutic alliance and competent general psychiatric care, just as we have all been taught. Medications and psychotherapy have been proven to add to these general treatment effects, and it is likely that other commonly used add-ons do as well. Once again, common intuitions and media accounts are misleading and unbalanced. There is no reason for individuals with depression to give up on treatment. And once again, it is up to us psychiatrists to set the record straight.

Dr Morehead is a psychiatrist and director of training for the general psychiatry residency at Tufts Medical Center in Boston. He frequently speaks as an advocate for mental health and is author of Science Over Stigma: Education and Advocacy for Mental Health, published by the American Psychiatric Association. He can be reached at dmorehead@tuftsmedicalcenter.org.

The author would like to thank Ronald W. Pies, MD, for his review and thoughtful comments on an earlier draft of this article.

References

1. Leucht S, Hierl S, Kissling W, et al. Putting the efficacy of psychiatric and general medicine medication into perspective: review of meta-analyses. Br J Psychiatry. 2012;200(2):97-106.

2. Jakobsen JC, Gluud C, Kirsch I. Should antidepressants be used for major depressive disorder? BMJ Evid Based Med. 2020;25(4):130.

3. Fountoulakis KN, Hoschl C, Kasper S, et al. The media and intellectuals' response to medical publications: the antidepressants' case. Ann Gen Psychiatry. 2013;12(1):11.

4. Dominus S. Does therapy really work? Let’s unpack that. The New York Times Magazine. May 16, 2023. Accessed December 14, 2023. https://www.nytimes.com/2023/05/16/magazine/does-therapy-work.html

5. Moyer MW. How much do antidepressants help, really? The New York Times. April 21, 2022. Accessed December 14, 2023. https://www.nytimes.com/2022/04/21/well/antidepressants-ssri-effectiveness.html

6. Kirsch I. The Emperor’s New Drugs: Exploding the Antidepressant Myth. Basic Books; 2011.

7. Moncrieff J. Against the stream: antidepressants are not antidepressants–an alternative approach to drug action and implications for the use of antidepressants. BJPsych Bull. 2018;42(1):42-44.

8. McBain S. Joanna Moncrieff: “I’m not convinced antidepressants have any use.” The New Statesman. April 22, 2023. Accessed December 14, 2023. https://www.newstatesman.com/the-weekend-interview/2023/04/joanna-moncrieff-im-not-convinced-antidepressants-have-any-use

9. Cuijpers P, Turner EH, Mohr DC, et al. Comparison of psychotherapies for adult depression to pill placebo control groups: a meta-analysis. Psychol Med. 2014;44(4):685-695.

10. Brown H. Looking for evidence that therapy works. The New York Times. March 25, 2013. Accessed December 14, 2023. https://archive.nytimes.com/well.blogs.nytimes.com/2013/03/25/looking-for-evidence-that-therapy-works/

11. Leichsenring Falk, Steinert C, Rabung S, Ioannidis JPA. The efficacy of psychotherapies and pharmacotherapies for mental disorders in adults: an umbrella review and meta‐analytic evaluation of recent meta‐analyses. World Psychiatry. 2022;21(1):133-145.

12. Kelley JM, Kaptchuk TJ, Cusin C, et al. Open-label placebo for major depressive disorder: a pilot randomized controlled trial. Psychother Psychosom. 2012;81(5):312-314.

13. Pies RW. Are antidepressants effective in the acute and long-term treatment of depression? Sic et Non. Innov Clin Neurosci. 2012;9(5-6):31-40.

14. Rutherford BR, Roose SP. A model of placebo response in antidepressant clinical trials. Am J Psychiatry. 2013;170(7):723-733.

15. Khan A, Brown WA. Antidepressants versus placebo in major depression: an overview. World Psychiatry. 2015;14(3):294-300.

16. Munder T, Flückiger C, Leichsenring F, et al. Is psychotherapy effective? A re-analysis of treatments for depression. Epidemiol Psychiatr Sci. 2019;28(3):268-274.

17. Kirsch I, Deacon BJ, Huedo-Medina TB, et al. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 2008;5(2):e45.

18. Cuijpers P, van Straten A, Hollon SD, Andersson G. The contribution of active medication to combined treatments of psychotherapy and pharmacotherapy for adult depression: a meta‐analysis. Acta Psychiatr Scand. 2010;121(6):415-423.

19. Gao K, Wang Z, Chen J, et al. Should an assessment of Axis I comorbidity be included in the initial diagnostic assessment of mood disorders? Role of QIDS-16-SR total score in predicting number of Axis I comorbidity. J Affect Disord. 2013;148(2-3):256-264.

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