Rutherford, B.R., Pott, E., Tandler, J.M., Wall, M.M., Roose, S.P., & Lieberman, J.A. (2014). Placebo response in antipsychotic clinical trials: A meta-analysis. JAMA Psychiatry, doi:10.1001/jamapsychiatry.2014.1319.
The placebo response refers to improvements in symptoms among participants in medication trials that cannot be specifically attributed to the active ingredient of the intervention. For this reason, it is common to have a placebo control condition in trials of medications. In these trials, some participants are randomly assigned to the medication condition, and some are randomly assigned to a placebo control condition. Typically, the placebo is a pill that looks exactly like the medication but that has no active ingredient. Both patients and providers are blind or unaware of whether the patient is receiving the active medication or the placebo. The placebo response is usually attributed to a number of sources: (1) the patient’s expectation of receiving benefit, (2) the patient’s contact with a caring provider and the healing effect of factors like therapeutic alliance and provider empathy, (3) statistical and measurement error, and (4) random changes in patient symptoms that are unrelated to the medication or the placebo. The first two sources are psychological factors that are often specifically active and purposefully enhanced in psychotherapies. That is, some psychotherapists actively work to develop an alliance with the patient and to align therapeutic interventions with patient expectations and preferences. (For a broader discussion, see my review of Common Factors in this month’s PPRNet blog.) The placebo response can sometimes be quite powerful such that antidepressant medications, and antipsychotic medications for example, only tend to be modestly superior to placebo. People with schizophrenia have cognitive difficulties that may reduce their expectations of receiving benefits from treatment. These patients also have significant interpersonal difficulties so that their alliance with health care providers may be significantly hampered. For these reasons, it may be possible that the placebo response may play a smaller role in the medical treatment of patients with schizophrenia. Rutherford and colleagues conducted a meta analysis of 105 studies of over 24,000 participants from 1960 to the present. Their goal was to examine if the average drug-placebo difference decreased significantly over time (i.e. across years of publication). They found that the placebo response significantly increased from 1960 to the present. That is, the average placebo patient tended to get worse in the 1960s, but by the 2000s the average placebo participant tended to get better. The effect of this trend was large (r = .52). By contrast, treatment change associated with antipsychotic medications decreased over time, and the effect of this trend was moderate (r = -.26). The authors suggested possible explanations for this trend. The average participant in drug trials in the 1960s was more severely ill than the average patient enrolled in drug trials in the 2000s. It is possible that the placebo response is more powerful in less severely ill individuals. Also, the authors suggested that a number of study design factors (e.g., multi site vs single site trials, financial incentives to recruit more patients may result in less severely ill and younger samples) may also contribute to this trend.
One of the practical implications of these findings is that drug companies may be less inclined to fund research and development of new medications for mental illnesses if the research is increasingly showing only modest benefits over control conditions. On the other hand, health care workers who provide: support and empathy, a positive therapeutic alliance, positive expectations about benefits of treatment, attention to patient preferences, and a coherent narrative to understand their patient’s illness may help to enhance the effects of interventions including antipsychotic medications. This may be especially true for younger and less severely ill individuals with schizophrenia.