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Razza, L. B., Moffa, A. H., Moreno, M. L., Carvalho, A. F., Padberg, F., Fregni, F., & Brunoni, A. R. (2018). A systematic review and meta-analysis on placebo response to repetitive transcranial magnetic stimulation for depression trials. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 81, 105-113.

Transcranial magnetic stimulation (TMS) is a new treatment for depression thought to modulate brain activity through electromagnetic pulses delivered by a coil placed over the patient’s scalp. A meta analysis shows that TMS may be effective in treating depressive disorders when compared to a placebo control, although only 18.6% of those receiving TMS were no longer depressed at the end of treatment. The placebo control condition usually involves a sham version of TMS in which the coil is placed over the scalp but no magnetic stimulation is applied. In antidepressant trials, the placebo response is quite high such that approximately 40% of patients respond to the placebo condition (in antidepressant trials, the placebo condition includes an identical pill that is inert). In this meta analysis, Razza and colleagues assess the placebo response in TMS. They included only double blind randomized controlled trials (i.e., trials in which both the patient and physician were not aware if the treatment was real or a sham). The authors estimated the placebo response based on pre- to post-sham TMS scores of common measures of depression. The meta analysis included 61 studies of over 1300 patients. The main result showed that sham response was large (g = 0.80; 95%CI = 0.65–0.95). Trials including patients with only one episode of depression or who were not treatment resistant (g =0.67, 95%CI = 0.06–1.28, p= 0.03) had higher placebo responses than those trials in which patients previously had two or more failed antidepressant treatments (g = 0.5, 95%CI = 0.03–0.99, p = 0.048).

Practice Implications

The results of this meta analysis demonstrates a high placebo response in trials testing TMS. This is similar to the high level of placebo response commonly seen in patients in antidepressant medication trials. It appears that psychological factors like attention, instillation of hope, patient expectations of receiving benefit, and perhaps working alliance may account for an important portion of why pharmacological and other medical interventions appear to work for those with depressive disorders. This is particularly true for patients who are receiving treatment for the first time or for whom previous medical treatment was successful.

Greenberg, R.P. (2016). The rebirth of psychosocial importance in a drug-filled world. American Psychologist, 71, 781-791.

In this thoughtful piece, Greenberg reviews the research on psychosocial factors that affect mental health treatment outcomes – including for medications and in psychotherapy. There has been an important shift in the last few decades to view mental disorders, including depression, as biologically based. For example, surveys indicate that the public’s belief in biological causes of mental illness rose from 77% to 88% during a 10 year period. During the same period the belief in the primacy of biological treatment for mental disorders rose from 48% to 60%. Further, 20% of women and 15% of men in the US are currently taking antidepressant medications. Some of these trends are due to direct to consumer marketing of medications by the pharmaceutical industry, which saw a 300% increase in sales in antidepressants. Some of these trends are also due to Federal agencies like the National Institute of Mental Health that vigorously pursued an agenda of biological research. But what is the evidence for a purely biological view of mental health? Greenberg notes that the evidence is poor. For example, no one has been able to demonstrate that a chemical imbalance actually exists to explain depressive symptoms – which undermines the reason for using medications to treat depression. Further, research on the efficacy of antidepressant medications shows that they perform only slightly better than a placebo pill, prompting a former editor of The New England Journal of Medicine to declare that this difference is unlikely to be clinically meaningful. The placebo effect is essentially a psychosocial effect. It refers to: the patient’s experience of a caring relationship with a credible professional, and the patient’s expectations and hopes of getting better. Placebo is a very real phenomenon that also has an impact on purely medical interventions like surgeries. In psychotherapy trials, relational/contextual factors like therapeutic alliance, expectations, therapist empathy, and countertransference likely account for more of the client’s outcomes than the particular therapeutic technique that is used. In both psychotherapy and medication treatments for depression, it appears that the more patients perceived their doctors as caring, empathic, open, and sincere, the greater their symptom improvement. There is also good evidence that psychotherapy is as effective and antidepressants for mild to moderate depression, and that antidepressants are slightly superior for chronic depression. However, even the latter should be interpreted carefully and within the context that patients prefer psychotherapy, their adherence to medications is poorer, side effects are worse for medications, and drop out rates are lower for psychotherapy.

Practice Implications

Patients benefit from antidepressant medications, but perhaps not exactly for the reasons that they are told. Psychosocial factors likely account for a large proportion of the effects of many medically-based interventions for mental disorders. Psychosocial factors are actively used in many psychotherapies, and therapists’ qualities like their ability to establish an alliance, empathy, and professionalism account for a moderate to large proportion of why patients get better.

Furukawa, T.A., Cipriani, A., Atkinson, L.A., Leucht, S., Ogawa, Y., … Salanti, G. (2016). Placebo response rates in antidepressant trials: A systematic review of published and unpublished double-blind randomised controlled studies. Lancet Psychiatry, 3, 1059-1066.

The placebo response in medication trials is an interesting and important phenomenon. Placebo response refers to improvement in clients that is due to therapeutically powerful factors like client’s expectations that an intervention will be effective and to the therapeutic relationship with the health care provider. In medication trials, placebo is seen as problematic because researchers typically want to demonstrate the effectiveness of the active medication (e.g., selective serotonin re-uptake inhibitors) independent of any other factors. For this reason, randomized clinical trials of medications are often double-blind and placebo controlled (i.e., clients and clinicians are unaware of who received the active medication and who received the inert placebo pill). It has widely been suspected that over the years the placebo response has been increasing in antidepressant trials possibly due to the types of patients included in trials (i.e., more recently, patients with more severe symptoms are included) and to other methodological issues (e.g., use of multi-centre trials, dosing schedule). An increasing placebo response is suspected of contributing to the growing number of failed anti-depressant trials (i.e., trials that show little or no effectiveness of the medication). Using advanced statistical methods, Furukawa and colleagues evaluated in a meta analysis if placebo response in medication trials was increasing over time. They defined a response as a 50% or greater reduction in observer-rated depression scale scores from baseline to 8 weeks. Their review included 252 placebo controlled trials of antidepressants from 1978 to 2015. Placebo response rates ranged widely from 0% to 70% (I² = 74.1%) with a mean placebo response of 35% to 40%. Year of publication was not significantly related to placebo response rate after controlling for methodological variables like length of the trial, multi-centre trials, and dose regimen. That is, once change in the methodology of conducting trials over time was accounted for, the placebo response appeared to remain largely the same from year to year.

Practice Implications

The placebo response is very real and complicates our understanding of how and why antidepressants might work for some patients. About 35% to 40% of patients who benefit from antidepressants may be benefitting largely because of the expectation of getting better. Greater treatment response to antidepressants for a large proportion of patients appears to be dependent on the therapeutic features of supportive contact with a caring health professional.

The Great Psychotherapy Debate: Since April, 2015 I review parts of The Great Psychotherapy Debate (Wampold & Imel, 2015) in the PPRNet Blog. This is the second edition of a landmark and sometimes controversial book that surveys the evidence for what makes psychotherapy work. You can view parts of the book in Google Books.

A couple of decades ago Martin Seligman famously said: “Whenever you hear someone demanding a double-blind study of psychotherapy, hold on to your wallet.” In this chapter, Wampold and Imel continue their examination of the Medical Model versus the Contextual Model for psychotherapy by discussing the viability of double-blind placebo control designs in psychotherapy. This topic sounds a little esoteric, but it’s not – this issue reaches into the very core of the definition of psychotherapy. A placebo-controlled trial in medicine often involves comparing a medication that contains an active biochemical ingredient versus a “sugar pill” that is exactly like the medication but without the active biochemical ingredient. Key to the placebo controlled design is that the health care provider, the patient, nor the researcher/evaluator knows which patient received which pill (i.e., the classic “double-blind” design). However, double-blinding is impossible in psychotherapy – the therapist must know what they are providing, which means that they know which treatment is expected to be effective, and which treatment is favoured by the researchers. Further, the researchers know which patients are getting which intervention of study condition. This affects a critical aspect of psychotherapy, that is, the therapist’s ability to provide a good rationale for the disorder and for the efficacious actions of the therapy. Additionally, patients are often aware that they are getting a pseudo-treatment in the placebo, and so their expectation of outcomes is also lowered (actually, this is often true in medical trials as well as most medications have side effects, and the absence of a side effect signals to the patient and the researcher that the patient is receiving the placebo). Wampold and Imel argue that common factors like emotional arousal, an acceptable explanation of the disorder, an understanding and empathic therapist, a structure to the treatment, and therapist and client expectations and hope are integral to the effectiveness of psychological therapies. They further argue that these are the very factors that medical trials try to control with a double-blind placebo controlled trial. Nonetheless placebo-like controls have been tried in psychotherapy to test the active or specific ingredients of a therapy – that is, to isolate the effects of active ingredients from the relationship context of the therapy. Placebo-like controls in psychotherapy have been called: minimal treatment, supportive counselling, non-directive counselling, etc. However, as mentioned, these placebo control conditions often contain elements that are integral to the effectiveness of psychotherapy, like: emotional arousal, an empathic therapist, and client expectations. And so not surprisingly, after reviewing meta-analyses of placebo-like conditions in psychotherapy research, Wampold and Imel conclude that when the studies are well constructed, these placebo-like conditions perform nearly as well as evidence-based treatments.

Practice Implications

What is the take home message for the clinician of this seemingly esoteric topic about research design? Although the placebo-controlled double-blind randomized design is the gold standard in medical research, this design is not possible or even logical for psychotherapy. The relationship, therapist factors, expectations, and contextual factors that one tries to control in a placebo-controlled trial are some of the very ingredients that are active in psychotherapy. The technical and specific ingredients of psychotherapies (e.g., transference interpretations, cognitive restructuring, two-chair techniques, etc.) are also part of the mix; but in the end, one cannot separate contextual relationship factors from techniques when it comes to providing psychotherapy.

The Great Psychotherapy Debate: Since in April, 2015 I review parts of The Great Psychotherapy Debate (Wampold & Imel, 2015) in the PPRNet Blog. This is the second edition of a landmark, and sometimes controversial, book that surveys the evidence for what makes psychotherapy work. You can view parts of the book in Google Books.

Wampold, B.E. & Imel, Z.E. (2015). The great psychotherapy debate: The evidence for what makes psychotherapy work (2^nd edition). New York: Routledge.

In this part of the book, Wampold and Imel discuss the importance of client expectations on psychotherapy outcomes. In particular, they equate client expectations with the placebo effect. In the July, 2015 PPRNet blog, I discussed Wampold and Imel’s distinction between the Contextual Model of psychotherapy and the Medical Model of psychotherapy. One pathway of the Contextual Model indicates that patients who accept an explanation for their disorder and who agree with therapists about therapy interventions, experience expectations that have a powerful impact on patients’ emotions and cognitions. The placebo effect has long been known to improve patients’ response to medical interventions. The placebo effect is defined as the difference between a supposedly inert event or medication and the natural course of the disorder. By contrast, the specific effect of an intervention or medication (e.g., an antidepressant) is defined as the difference between the medication and the placebo (i.e., the effect of a medication over and above the effect of a placebo). In one important meta analysis, the placebo effect accounted for about 68% of the antidepressants’ impact on depression scores. In other words, the placebo effect (i.e., the expectation of receiving help) has a powerful impact on depression. Generating an expectation of improvement (“this pill is an antidepressant that will reduce your depression”) involves: (1) providing a plausible explanation for the disorder (“depression is biochemical imbalance, and this pill [actually an inert placebo] will help”), and (2) having a relationship with an empathic provider. Client expectations of improvement result in mental health outcomes that approach the effects of standard medical treatment for depression. In psychotherapy, creating expectations about the effectiveness of the intervention, providing an explanation of the disorder based on psychological and biological theories, and agreeing on the tasks and goals of therapy are an integral part of the treatment. In other words, the placebo response is part of what makes psychotherapy work, and good therapists capitalize on its effects.

Practice Implications

Patient expectations about the effectiveness of the therapy, their agreement with the therapist on the tasks and goals of therapy, and the therapist’s empathy toward the patient are key aspects that will increase the effectiveness of a therapeutic intervention. The explanation of the disorder and the treatment approach are embedded in psychological theories that typically underpin evidence-based psychotherapies.