Participants
This trial will include patients who meet the following criteria.
Inclusion criteria:
Primary diagnosis of persistent depressive disorder according to DSM-5
Aged 18–70 years
No current psychotherapeutic treatment
Written consent to participate in the study
Exclusion criteria:
Αcute suicidality
Substance abuse or dependence syndrome within the past 3 months
Psychotic disorders or symptoms of bipolar disorder
Borderline personality disorder
Organic mental disorder or serious physical illness
Concurrent psycho-pharmacological treatment is not an exclusion criterion. Patients continue to receive a pharmacological anti-depressant treatment if it is indicated and are encouraged to keep it constant. Changes in the type and dose of the medication are recorded and documented. The waiting period for the wait-list control group is comparable to the usual waiting time for patients in outpatient psychotherapy care in Germany.
Participants will be excluded from the study if:
The participant requests it (withdrawal of consent for participation)
Further participation is associated with risks to the mental condition of the patient
The participant’s condition requires inpatient treatment
Participants may withdraw from the study for any reason at any time. The principal investigator also may withdraw participants from the study in order to protect their safety or if they are unwilling or unable to comply with required study procedures. If a patient’s condition requires further treatment after withdrawal from the study or after completion of the program, the patient will be offered psychotherapy at the Center for Psychotherapy of the Goethe University Frankfurt or alternatively will receive support to find appropriate counseling or health care.
Sample size
Previous within-group design studies [
35,
38] showed moderate to large pre-post effect strengths of the group meditation program. The expected effect size for wait-list controlled studies cannot be derived from within-group design studies. However, given the expectations that a wait-list control group of patients with chronic depression will not change over the waiting period, and that the additional individual treatment component may increase the efficacy of the group meditation treatment, we assume at least a moderate effect of f = 0.25 in comparison to the wait-list control group. A power analysis was computed using G-Power 3.1.9.2 [
56], with repeated measures ANOVA (within–between interaction) with two measurement time points, a power of 0.80, a strict α error probability of 0.01, and a correlation among the repeatedly measured dimensions of r = 0.7 [
57], resulting in a sample size of 34 (using effect size specification as in SPSS). Hence, including a supposed drop-out rate of 25%, at least 46 patients must be recruited for this study. In order to realize group treatments with traditional group sizes (8–12 participants), we decided to perform the trial with two rounds or
cohorts with equal size, each with one treatment and one wait-list control group. During the first round of the trial, half of the participants (cohort 1) will be recruited, randomized, and receive treatment or be in the wait-list control group. This procedure will be repeated in the second round with the second half of the participants (cohort 2). As a result, we will have a total of four therapy groups (two times one treatment and one control group). Since we strive for balanced therapy group sizes, we will include 12 participants per therapy group, i.e., 4 × 12 = 48 participants in total.
We would like to mention that as a result of this procedure we will have a stratification variable “cohort”. Since this stratification variable will be included only for administrative reasons, we will not include it in our statistical models [
58].
An additional power analysis with the same parameters as above but with three measurements (including intermediate measurements), four groups (including a two-level stratification variable), and a less strict α error probability of 0.05 resulted in a sample size of 28.
Randomization
Participants will be randomly and uniformly allocated to two test conditions. We suppose that differences in the individual history of childhood maltreatment may have an influence on the effectiveness of the treatment. Therefore, to prevent imbalances between treatment groups, the sample will be stratified based on the two-level-factor “reported adverse childhood experience” as measured before randomization by the Childhood Trauma Questionnaire [
62]. Since we pursue the aim to inform participants about their allocation as soon as possible (see below), we decided to perform stratification and randomization as soon as half of the participants of one cohort (or one subcohort) have been enrolled. Thus, once 12 participants have been enrolled (subcohort 1 of 2), they are assigned to a stratum depending on their CTQ scores (“high level of childhood trauma/adversity” or “absence or low level of childhood trauma/adversity”). The CTQ cut-off values are set in advance. If odd numbers of participants are in the strata, the participant nearest the CTQ cut-off value will be assigned to the other stratum, despite not meeting the criteria for it. This procedure allows us to use random permuted blocks of even length (
n = 2, 4, 6, 8, 10, or 12) in the strata. These steps will be repeated with subcohort 2 (of 2). Hence, within each of these strata, participants will be randomly assigned to the treatment or to the control condition, producing equal therapy group sizes.
We will send anonymized participant codes via e-mail to an independent statistician, who will conduct randomization. Randomization will be carried out with computer-generated random lists created using Microsoft Excel®.
Blinding
Diagnosticians collecting observer rated measures will be blind to participant assignment as timing of assessments will be the same for all participants of a cohort. Blinding of diagnosticians should be maintained under all circumstances. To ensure that blinding is maintained, participants will be asked not to indicate their allocation status to the diagnosticians. Due to the design of the study, intervention blinding of participants and research workers, who also act as therapists, is not possible. The principal investigator is not blinded as he also implements the group therapies and individual therapies. Statistical analyses will be conducted by the authors, who will not be blinded or independent.
Interventions
In our study, two approaches are to be combined in an approximately 4-month treatment program: a metta-based group meditation program focusing on the meditation of mindfulness and metta (eight sessions of 120 min each + one half-day retreat), and an individual CBT program (eight sessions of 100 min each) based on CBT and schema therapy that emphasizes the transfer of the meditation program into daily life. The metta-based group treatment has been tested in a pilot study and has been slightly modified for this trial. An individual subsequent CBT treatment including behavioral activation, cognitive restructuring and—optionally—elements from schema therapy has been added to this trial. The traditional concept of behavioral activation [
63] was adapted to an interpersonal focus emphasizing self-confidence, positive social impact, and social interactions. Positive interpersonal behaviors are promoted based on personal values [
64], which helps to create a more positive attitude to oneself and others in concrete actions. The intervention also involves the development of an accepting attitude towards negative emotions and cognitions [
65], as well as actions involving benevolence to self and others [
29]. The practice of combining these interventions has been done informally by our work group in several cases of chronically depressed patients from our pilot studies [
35,
38] who had completed the studies but required additional treatment after termination of the study.
The mindfulness exercises are based on the manual of Segal, Williams, and Teasdale [
66] and include a body scan exercise, sitting meditation, and the breathing space exercise. A shortened sitting meditation form is the basis of the metta meditation and the starting point of the meditation exercises. The breathing space exercise is used especially in stressful everyday situations for a more conscious perception of thoughts, feelings, and body sensations. It will also be used to help participants distance themselves from rumination. To achieve maximum acceptance among all participants, esoteric terms were avoided in the instructions where possible.
The exercises for metta meditation are based on the manual of Kearney et al. [
67] using a German adaptation (Stangier U, Mendes A: Achtsamkeitsbasierte Loving Kindness Meditation, unpublished). The main aim is to focus on the perception of positive attitudes and feelings towards oneself and others. To elicit these positive emotions, kind wishes like “may (he/she/they/we/I) be safe/happy/live with ease/be free from suffering” are directed towards different recipients [
68]. Starting with oneself, the formulas are gradually extended to a friend, a neutral person, a person one has difficulties with, all four together, and finally to all human beings. In the group meditation program, the selection of the recipient and the formulas are individualized according to personal relevance. If participants experience difficulties with meditation—which is a natural part of it—they are instructed to develop a mindful (i.e., non-judgmental and observing) attitude towards negative thoughts and feelings related to the present moment. In addition, there are tasks related to reflection and discussions about benevolence, which generally have proven to intensify the motivation to behave benevolently towards others [
69]. The program also includes homework: daily meditation (at least once per day) and practice of benevolent behaviors, which shall be identified according to individual relevance, towards others and self. Participants receive audio recordings of guided meditations for their meditation homework. This should facilitate the correct learning of the meditation and ensure a standardization of this intervention component. Group treatment will be carried out by an approved psychotherapist and two clinical psychologists who are at an advanced stage of their post-graduate training in CBT.
The individual CBT following the group program is based on a manual for behavioral activation for depression [
65] and schema therapy [
54], both being adapted to the goals of the preceding meditation program.
The individual treatment part of the present trial will build on the experience gained from a randomized controlled clinical trial with patients with recurrent depression [
70]. In this previous study, an approach of combining individual setting elements of MBCT as well as Acceptance and Commitment Therapy (ACT) with activity scheduling and other behavioral techniques was applied [
71]. If patients report adverse memories about their childhood or other distressing events arising from dysfunctional schemas, techniques from schema therapy are used (e.g., schema diary, imagery rescripting, and empty chair dialogues).
Individual treatment will be carried out by two approved, experienced therapists and three clinical psychologists who are at an advanced stage of their post-graduate training in CBT. All therapists have received training in the treatment manual.
The participants will also be asked to respond daily to short electronic questionnaires throughout the project period. The questionnaire asks about the mood, whether the participants have meditated and, if so, how long and how well it worked. For this, text messages are sent with web links to the questionnaires. This has the function of a reminder but also of a meditation diary. In addition, these questionnaires will be evaluated weekly and give the study team and the therapist feedback on how the participants are adhering to the treatment. The questionnaires are located on the “unipark” platform and participants are asked to use their individual anonymized code to ensure protection of private participant data.
Data collection
Data from observer-rated measures will be collected by blinded, independent, trained clinical psychologists. The data will be logged on paper case report forms and afterwards independently entered by two project employees into a SPSS data sheet. All paper-based documents will be kept in a locked steel locker. Access to any data is restricted to trial personnel and investigators. The SPSS data sheet is stored on a secured server that is placed in a locked steel locker in a room accessible only by authorized IT personnel. The data values in the SPSS file are limited to appropriate ranges to ensure that only valid data are entered and will be checked for data entry mistakes.
Self-report measures, including all secondary outcomes except the OFD, will be collected by computerized questionnaires, using the academic online survey platform unipark [
84]. The program ensures complete data entry. To ensure anonymity, participants will receive an individual identification code for completing the questionnaires, for data storage, and for statistical analysis. Identification codes are stored on hard copies accessible only to the study administrators. The data gathered via unipark will be downloaded and included in the final SPSS data file.
Statistical analysis
The primary outcome measure is pre-post (i.e., T0–T2) changes on the QIDS-C. Intention-to-treat analyses will be employed in this trial. For the statistical analysis of the primary outcome we will use a three-factor mixed-design ANOVA with two two-level between-subjects factors (treatment and CTQ-based stratifier) and a two-level within-subjects factor (time, T0 and T2) in the model. For our primary outcome, the group difference at T2, we will use a model with an interaction of treatment by time. An additional analysis including T1 will be performed using planned contrasts to examine changes in depression after group and individual treatment. We will use a repeated measures MANOVA including a time by treatment interaction to assess the effects of secondary outcomes, which we assume to be moderately inter-correlated, followed by univariate repeated measures analyses.
An intended aim was to detect mechanisms of change, which requires a mediation analysis. However, mediation analyses using structural equation analyses and latent growth curve analyses require a larger sample size, more measurement occasions of potential mediators than given in our study, and the control of confounding variables between mediators and outcome [
88]. Therefore, exploratory regression analyses using pre-post differences in primary and secondary outcome after the meditation group treatment and the individual treatment will be performed to detect possible candidates for mediation analyses within future studies. Missing data will be handled using multiple imputation procedures. Data collected about adverse events and serious adverse events will be summarized by type and frequency, and regression analyses will be conducted to explore relations between adverse events and treatment. For statistical analysis, the computer program SPSS® (Statistical Package for Social Sciences, version 25) will be used.
Trial governance
The Trial Management Group consists of the principal investigator and the study team (two clinical psychologists and two graduate student research assistants) and will provide overall management of the study including set-up of the study, recruitment, training of independent clinical raters, providing treatment, and interpretation of results. Due to the small scale of our trial, no independent trials steering committee has been planned. Overall supervision of the trial is provided by the principal investigator. Weekly meetings of the project team are held and adherence to the study protocol is checked at regular intervals. Changes to the study protocol will be communicated to the funding source, the ethics committee, and the trial registry. No interim analysis is planned due to the small scale of the study. Therapists will be video-recorded during the group treatment sessions where participants give their consent. The treatment sessions will be supervised by the principal investigator in order to continuously ensure adherence to the study protocol. We will ask the therapists to give informal feedback and participants to give formal feedback on their experience and their acceptance of the treatment program via an anonymous paper-based questionnaire. The questionnaire consists of open-ended questions, which will be evaluated qualitatively.
Once a participant is enrolled, the Trial Management Group will make every reasonable effort to keep in contact with the participant during the entire study period. If a participant expresses doubts about further participation, a personal dialogue will be offered to him or her to possibly find a way to continue participating in the study. In order to pursue participant retention during the entire study period, prior to data collection time points participants will be contacted and reminded of the upcoming data collection. No further measures (e.g., material or financial incentives) are planned to promote participant retention. If participants withdraw from treatment or are excluded from interventions due to risk or otherwise deviate from the study protocol, we will attempt to collect all planned outcome data. We will only refrain from collecting outcomes from those who withdraw fully from the entire trial.
Adverse event monitoring
An adverse event is any untoward medical occurrence (e.g., a symptom or disorder) in a patient temporarily associated with our treatment. An adverse event does not necessarily have a causal relationship with the treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization, or results in persistent or significant disability/incapacity [
85]. Adverse events and serious adverse events will be collected throughout the trial and will be reported regarding type and time of occurrence. Collected data will be summarized by type and frequency, and regression analyses will be conducted to explore relations between adverse events and treatment. All therapists will be informed about potential adverse effects of meditation and will be encouraged to be particularly sensitive to this issue. The participants will be informed about possible side effects of psychotherapy and of meditation, and are encouraged to report negative changes.
All therapists involved in the trial are under continuous supervision by the principal investigator and will report weekly on suicidal ideations of patients or possible increase of risk for suicidal actions. Somatic conditions are checked by physicians prior to the participation in the study. Risk of side effects is considered low, but potential treatment-related adverse events will be carefully monitored. Medication will be checked regularly by psychiatrists consulted by the participants in the trial who take psychopharmacological drugs. Patients participating in the trial are instructed to keep their medication and change only after consulting their psychiatrist.
In an emergency, immediate contact with stationary psychiatric facilities in the Frankfurt area can be made. Since the interventions will be carried out by clinical psychologists and will be supervised by an experienced therapist, any worsening of the mental health condition of the participants can be detected and met accordingly.