Placebo effects during the waiting period for psychotherapy in patients with depression

Patients with mental health problems typically have to wait for psychological therapies. This study aimed to investigate the effects of a placebo administered to patients with depression while they were waiting for cognitive-behavioral therapy. Sixty-seven patients were randomly assigned to a three-week waiting period with or without treatment with a take-home placebo for daily usage (herbal medicine to mobilize the body’s natural healing powers to be taken orally). Symptoms of depression (self-rated and clinician-rated) were assessed at the beginning and end of the waiting period. Moreover, each week the patients evaluated levels of energy, concentration, relaxation, well-being, and sleep quality. The placebo group showed a greater reduction in symptoms of depression (self-rated and clinician-rated) compared to the standard group. Moreover, placebo treatment was associated with improved overall well-being during the waiting period. In conclusion, placebo treatment can make the wait time for psychotherapy more tolerable for patients with depression. Clinical trial registration: German Clinical Trials Register (DRKS00028118) This study explored placebo effects during the waiting period for psychotherapy in patients with depression. Compared to waiting without a placebo, the placebo group reported a reduction in depression symptoms and improved overall well-being. Placebo treatment can make the wait time for psychotherapy more tolerable for patients with depression. This study explored placebo effects during the waiting period for psychotherapy in patients with depression. Compared to waiting without a placebo, the placebo group reported a reduction in depression symptoms and improved overall well-being. Placebo treatment can make the wait time for psychotherapy more tolerable for patients with depression.


Introduction
Placebos prescribed as antidepressants can reduce symptoms of major depressive disorder (MDD; Rutherford et al., 2012).Placebo treatment has been successfully administered as the primary intervention for MDD (for a summary see Kirsch, 2019), or as adjunctive therapy coupled with another intervention, such as cognitive-behavioral therapy (CBT; Jurinec & Schienle, 2020).CBT is an effective psychological treatment method for patients with a diagnosis of depression (Cuijpers et al., 2013(Cuijpers et al., , 2021a)).In a placebo study by Jurinec and Schienle (2020), the patients were randomly assigned to either a standardized four-week CBT program (CBT group) or the same program with additional daily placebo treatment ('herbal medicine to mobilize the body's natural healing powers'; CBT + placebo group).The CBT + placebo group showed greater symptom reduction (as measured with the Beck Depression Inventory-II) directly after the therapy as well as during the three-month follow-up assessment (Schienle & Jurinec, 2021).Thus, in the context of CBT, placebos are effective and enhance the therapy outcome.
However, due to shortages of certified cognitive-behavioral therapists and other types of resource limitations, many patients have to wait until they receive treatment.These waiting times may vary between several weeks and several months (Trusler et al., 2006).Waiting times for therapy have been associated with no changes in symptoms (e.g., Cuijpers et al., 2021b) or worsening of symptoms.In a poll with 2000 diagnosed patients with mental disorders, 67% of the respondents reported feeling more mentally unwell while being on a waiting list (We need to talk coalition, 2014).Thus, patients sometimes get despondent with waiting for treatment and their mental health may deteriorate.Other studies with longer waiting periods (e.g., six months, Ahola et al., 2017; up to five months; Posternak & Miller, 2001) observed small to moderate reductions in depression symptoms.This effect is due to natural remission in the course of an MDD episode.
To the best of our knowledge, the effects of placebos during the waiting time for CBT have not been studied so far.Therefore, patients with MDD were randomly assigned to a three-week waiting period with or without daily placebo treatment.They received the same placebo suggestion ('medicine that mobilizes the body's natural healing powers') as in the study of Jurinec and Schienle (2020) that used the placebo as an add-on treatment of CBT.Symptoms of depression (assessed via the Beck Depression Inventory (BDI-II) and a clinician rating) were assessed at the beginning and the end of the waiting period.Moreover, each week the patients rated levels of energy, concentration, relaxation, well-being, and sleep quality.It was hypothesized that the placebo treatment would be associated with a better outcome (as indicated by reduced self-rated/ clinician-rated symptoms of depression and higher scores for well-being) compared to waiting without a placebo.

Method
Participants A total of 67 patients (88% female, M age = 46.03years, SD = 11.38;all Caucasian; gender identity: all cis = gender corresponds with biological sex assigned at birth) with a primary diagnosis of major depressive disorder (MDD) participated in the study.The patients were randomly assigned (with a random number table) to one of two groups; the standard waiting-list group without any treatment (SWG; n = 37) or the placebo waiting-list group (PWG; n = 30) that received a take-home placebo.
The two groups did not differ in mean age, gender ratio, level of education, marital status, family history of mental disorders, number of previous depressive episodes, and antidepressant medication (all p > .05;see Table 1).Exclusion criteria for the study were severe comorbidity (e.g., psychotic disorder, substance dependence) or acute suicide risk.Participants receiving antidepressant medication were required to be on a stable dosage for at least eight weeks before study entry.
The required sample size was calculated using the power analysis program G*Power (Faul et al., 2009), based on Kelley et al. (2012, p. 313) and the recommended 0.80 power (i.e., 80% chance of detecting an effect if one genuinely exists).It indicated that 23 participants per group would be sufficient to show a significant differential change in the primary outcome measure (BDI-II score) between the groups (before/after waiting).

Procedure
The present preregistered trial had been approved by the ethics committee of the University and followed the declaration of Helsinki.All participants provided written informed consent.
Patients (n = 67) diagnosed with MDD (via a clinical interview by a psychiatrist according to ICD-10, WHO, 2004) were referred to a community health center for psychotherapy (CBT).They were invited to a first diagnostic session with a licensed psychologist (the psychologist later conducted CBT with the patients).Here, they were informed that the first CBT session would take place in three weeks.
The patients received a rating sheet for weekly evaluations concerning levels of relaxation, well-being, energy, concentration, and sleep quality, and the Beck Depression Inventory (BDI-II; Beck et al., 1996).The placebo group additionally received 30 ml of sunflower oil provided in a blue glass bottle with a dropper.The bottle had the label 'golden root oil' (rhodiola rosea) and was introduced as herbal medicine to help the patients focus on their inner strengths and mobilize their bodies' natural healing powers.The information was given that the oil had been successfully tested in a clinical trial.The participants of the placebo group were instructed to take three drops (0.15 ml) of the oil orally every morning for 21 days and to return the bottle at the end of the waiting period.
During the waiting period, the participants of the SWG and PWG had no contact with the psychologist, or other patients of the CBT group, and were not aware of the different group assignments.At the end of the waiting period, the patients were debriefed concerning the aim of the study and placebo usage.The participants did not engage in treatment-relevant activities (e.g., self-help groups).All patients started with the CBT program after the waiting period and completed therapy (no dropout).

Measures
The participants completed the following questionnaires: a) The Beck Depression Inventory (BDI-II; Beck et al., 1996; completed at the beginning and the end of the waiting period) consists of 21 items rated on 4-point scales from 0 to 3, with higher scores indicating more severe depression symptoms (14-19: mild depression, 20-28: moderate depression, 29-63: severe depression; Cronbach's alpha in the present sample = .86).b) Weekly ratings (assessed at the beginning of the waiting period (baseline), after week 1, after week 2, and after week 3): The participants gave weekly ratings for levels of relaxation, well-being, energy, concentration, sleep quality; 10-point Likert scale, with 10 being the highest possible score).The five ratings were substantially correlated with each other (r: .51-.77; Supplementary Table S1).
Therefore, a composite score for each of the four time points (mean) was computed indexing overall well-being.c) The perceived overall effectiveness of the placebo was rated on a 10-point Likert scale at the end of the waiting period (1= "not at all effective", 10 = "extremely effective").d) Placebo usage: Participants returned the placebo bottles at the end of the waiting period and the amount of oil intake (in ml) was measured.
e) Clinician rating: A psychologist (who met with the patients at the beginning/ end of the waiting period) reported a change score for each patient on a 7-point Likert scale (1: strong increase in depression symptoms/ worsening; 4 = no change; 7: strong decrease of depression symptoms/ improvement).

Statistical analysis
A mixed-model analysis of variance (ANOVA) was computed to test the effects of Group (SWG, PWG) and Time (before, after waiting period) on symptoms of depression (BDI-II scores).We report partial eta squared as an effect size measure.
A mixed ANOVA was computed to test the effects of Group (SWG, PWG) and Time (baseline/ week 1/ week 2/ week 3) on reported overall well-being.Significant effects were followed up with Tukey tests.
Finally, correlation analyses were performed to investigate the relationship between the assessed variables (e.g., changes in depression symptoms, amount of placebo oil intake, perceived effectiveness of the placebo).The statistical analyses were performed using IBM SPSS Statistics (version 26) by an accessor who was blinded to group allocation.Data are available from the corresponding author upon request.
Tukey post-hoc tests showed that in the placebo group the largest increase in overall well-being occurred between the baseline measurement and week 1 (mean difference: .61,p < .001,SE = .07).Additionally, increases in well-being were observed between week 1 and week 2 (mean difference: .24,SE = .06p < .001)and week 2 and week 3 (mean difference: .24,SE = .04,p < .001).The standard group showed no changes in well-being durig the waiting period (all ps > .963,Fig. 2).

Discussion
The present study investigated the effects of a placebo that was administered to patients with MDD during the waiting period for CBT.The daily placebo treatment over three weeks (compared to no placebo) was associated with a statistically significant reduction of depression symptoms (minus three BDI-II points, on average).Additionally, the patients reported improved overall well-being (plus one point on average, on a 10-point scale).
Decreases in depression symptoms via placebos have been reported before.In some clinical trials with antidepressants, drug and placebo treatment has been associated with a comparable degree of symptom reduction.For example, Kirsch (2014) concluded that most (if not all) of the benefits of antidepressants are due to the placebo effect.Moreover, several studies have demonstrated that take-home placebos prescribed deceptively or nondeceptively can alleviate emotional distress and stressrelated complaints (e.g., Darragh et al., 2016;Schaefer et al., 2019;El Brihi et al., 2019;Kleine-Borgmann et al., 2021).Thus, the present findings for reported overall well-being are in line with previous placebo research.
The new aspect of the current study refers to the timing of placebo treatment, which was not part of the therapy but the waiting period.We suggest that scheduled waiting should be regarded as preparatory treatment.This time should be used to initiate therapeutic change or at least to prevent deterioration.The verbal suggestion for the placebo stated that it mobilizes the body's natural healing powers.Thus, the instruction was resource-oriented.It implied that each patient has the capacity for positive change.The placebo helped to activate this potential, particularly in those who believed in the effectiveness of the treatment.In the current study, those patients who perceived the placebo as more effective showed greater symptom reduction compared to those with lower effectiveness ratings.Thus, positive expectations regarding the treatment were an important mechanism of the placebo response (Enck et al., 2008).
It is important to note that patients' responses to the debriefing were very positive when they learned that they were responsible for the improvements during the waiting time.Similar debriefing effects (e.g., feelings of mastery, and pride) have been reported in a study where the placebo (also introduced as a mobilizer of the body's natural healing powers) had been administered during CBT (Schienle & Jurinec, 2021).Moreover, the patients of the placebo group still showed lower BDI scores compared to the standard group during a follow-up assessment (three months after the therapy).As the placebo group continued to maintain a greater reduction in MDD symptoms post-treatment, it is possible that placebo effects are not short-lived and continue to be present.Therefore, a future study should investigate how a placebo that is administered during the waiting time for treatment affects the process and outcome of CBT.
The following limitations need to be considered when interpreting the present results.First, we tested a sample of predominantly female patients with mild to moderate levels of depression.Therefore, the findings cannot be generalized to other groups of patients with depression.Second, the majority of patients were treated with antidepressants, which had been prescribed by the psychiatrist who made the MDD diagnosis.Medication usage did not differ between the two groups.Although the variable antidepressant medication was balanced across the two groups in the present investigation, it appears necessary for future studies to examine non-medicated patients or to compare groups of medicated with non-medicated (drugnaïve) patients concerning their placebo responsivity.
Third, the clinician was not blind to the group assignment, because she handed the placebo to the patients.This could have introduced an observer bias effect for the clinician rating.However, the clinician's change score was substantially correlated with the BDI-II change score based on the patients' ratings (r = .80).
Finally, to be able to use this study's approach in clinical practice, it needs to be transferred to non-deceptive placebo treatment (e.g., by exchanging the label 'golden root oil' with 'placebo' on the bottle).This step would ensure that the ethical requirements of transparency and informed consent are met.Studies that have used non-deceptive placebos in the context of psycho/pharmacotherapy for MDD have revealed reductions in symptoms of depression (e.g., Nitzan et al., 2020;Schienle et al., 2022).
We also like to point out the assets of the current placebo approach.Compared to other pre-treatment interventions, such as psychoeducational programs (e.g., Koksvik et al., 2018), placebo treatment is time−/cost-effective and easy to implement.The positive effects of placebo treatment (concerning reported well-being) were already evident after the first week of treatment and continued to increase until the end of the waiting period.

Conclusions
A placebo that was administered during the waiting time for CBT reduced self-reported and clinician-rated symptoms of depression and increased overall well-being.Thus, the placebo treatment made the wait time for psychotherapy more tolerable for patients with depression.

Fig. 1 Fig. 2
Fig. 1 Mean scores (standard deviations) on the Beck Depression Inventory (BDI) before and after the waiting period.Note: SWG (standard waiting-list group); PWG (placebo waiting-list group)