1 INTRODUCTION

Major depressive disorder (MDD) is a common psychiatric disorder affecting more than 350 million people worldwide (Marcus et al., 2012). MDD has the highest burden of psychiatric disorders in high-income countries and is expected to have the second-highest burden worldwide in 2030 (Mathers & Loncar, 2015; Sobocki et al., 2006). MDD is associated with a 50%–80% lifetime recurrence rate, therefore reduction of relapse risk is important.

Mindfulness-based cognitive therapy (MBCT) is an established intervention for patients with recurrent depression, combining elements of cognitive-behavioral therapy (CBT) and mindfulness-based stress reduction (Beck et al., 1979; Godfrin & Heeringen, 2010; Kabat-Zinn, 1990; Ma & Teasdale, 2004; Piet & Hougaard, 2011; Teasdale et al., 2000). MBCT is expected to reduce the engagement in repetitive negative thinking patterns of patients with recurrent depression, which already seem to occur during a mildly negative mood (Nolen-hoeksema, 1991). There is evidence that MBCT changes cognitive reactivity (CR), rumination, self-compassion, and mindfulness. There is growing evidence that these factors are indeed mediating the reduced relapse risk by MBCT (Cladder-Micus et al., 2018; Frostadottir & Dorjee, 2019; Gu et al., 2015; Van der Velden et al., 2015). CR is the vulnerability to indulge in patterns of negative thinking when experiencing (mild) dysphoric mood states (Figueroa et al., 2015; Segal et al., 2006; Van der Does, 2002). Rumination refers to repetitive and passive thoughts about one's negative feelings and symptoms (Nolen-hoeksema, 2000). Self-compassion is the capacity to respond kindly and compassionately to oneself when facing difficult situations (Neff, 2003). Mindfulness refers to the capacities of bringing one's deliberate attention to present moment experience with a kind, non-judging attitude (Baer et al., 2006).

Two important clinical factors associated with relapse are the number of previous episodes and the presence of residual symptoms (Hardeveld et al., 2010). In addition, CR measured by the self-rated Leiden Index of Depression Sensitivity (LEIDS; Van der Does, 2002) and its subscale ‘rumination' were associated with relapse, in patients with ≥MDD-episodes (Elgersma et al., 2015; Figueroa et al., 2015; Moulds et al., 2008). Moreover, rumination and mindfulness after MBCT were associated with relapse after a 12-month follow-up (Michalak et al., 2008, 2011). Self-compassion also seems to be associated with depressive symptoms (López et al., 2018), but its association with relapse has not yet been investigated. Clinically, one would like to know how CR, rumination, self-compassion, and mindfulness are associated with future relapses of MDD-episodes in a patient group receiving MBCT.

Although maintenance antidepressant medication (mADM) significantly reduces the risk of relapse, this risk returns after stopping them (Geddes et al., 2003). Patients are often reluctant of long-term mADM usage, due to (fear of) side-effects or the perception that it would be difficult to discontinue ADM after long-term use (Sansone & Sansone, 2012). MBCT could be effective to reduce relapse risk after mADM discontinuation (Tickell et al., 2020). By investigating the effect of mADM discontinuation on the association of relapse with CR, rumination, self-compassion, and mindfulness clinicians could additionally indicate whether patients starting MBCT might be at higher risk when tapering their mADM.

Therefore, we aimed to examine whether baseline CR, rumination, self-compassion, and/or mindfulness are associated with future relapse/recurrence of MDD-episodes in a patient group receiving MBCT while either continuing or discontinuing their mADM.

2 MATERIALS AND METHODS 2.1 Design

We used data from two multicentre, randomized controlled trials (the MOMENT-study; Huijbers et al., 2012) approved by the CMO Arnhem-Nijmegen. The first trial consisted of patients who were randomly allocated to MBCT + mADM (n = 121) or MBCT + mADM discontinuation (n = 128), patients in the second trial were randomly allocated to MBCT + mADM (n = 33) or mADM alone (n = 35). For the current cohort study, we selected all participants allocated to MBCT, that is, those from the first trial (N = 249), plus the 33 patients allocated to MBCT + mADM from the second trial. All participants used mADM at the start of the trial and were offered eight weeks of MBCT. All participants gave written informed consent.

2.2 Participants

Participants were recruited via 12 universities and secondary healthcare centers across the Netherlands. Dutch speaking participants (>18 years) with a history of ≥3 depressive episodes according to the Diagnostic and Statistical Manual of Mental Disorders-4th edition (DSM-IV) were included; currently not meeting the criteria of a depressive episode assessed by the Structured Clinical Interview for DSM-IV (SCID); either in full (Inventory of Depressive Symptomology-Clinician (IDS-C) ≤ 11) or partial (IDS-C > 11) remission; and had been treated with mADM for ≥6 months. Exclusion criteria were: bipolar and/or primary psychotic disorder; clinically relevant neurological/somatic illness; current substance dependency; high dosage of benzodiazepines; electroconvulsive therapy in the past three months; previous MBCT and/or extensive meditation experience; and receiving frequent psychological treatment (more than once per 3 weeks).

2.3 Procedures

The SCID-I (First et al., 1996) was performed by trained research assistants to assess the eligibility of participants. After randomization and baseline assessment, MBCT started within 2 months after randomization. Follow-up assessments took place after 3, 6, 9, 12, and 15 months.

2.4 Interventions 2.4.1 Mindfulness-based cognitive therapy

MBCT was based on the protocol developed by Segal et al. (2013) with a few alterations to intensify the original treatment. The treatment consisted of eight weekly 2.5-h group sessions and one day of silence practice during the second half of the course. Participants were encouraged to practice meditation each day for 45 min. For further detail see the MOMENT study protocol (Huijbers et al., 2012).

2.4.2 Maintenance antidepressant medication

For all participants, mADM at the start of the study was reviewed by a study psychiatrist. For patients who were kept on mADM, psychiatrists maintained or reinstated an adequate dose of mADM and provided recommendations to manage side effects. Patients who were randomized to mADM discontinuation were seen by a study psychiatrist (3–12 visits). During the first MBCT week, patients were informed and prepared for mADM discontinuation. At Week 7, patients were asked to discontinue their mADM. For all common ADMs, a tapering scheme of 5 weeks was used and a specific withdrawal scheme for more exceptional treatments was determined from the shared opinion of the authors.

2.5 Study measures

Relapse was determined at each follow-up assessment via a SCID-I-interview (First et al., 1996). Table S1 summarizes the questionnaires measured at baseline. In brief, residual symptoms were measured with the IDS-C (Rush et al., 1996). CR was measured with the LEIDS-Revised (LEIDS-R; Van der Does, 2002). Previously, the rumination subscale appeared to be better associated with relapse than the LEIDS-total (Figueroa et al., 2015). Therefore, the total LEIDS-R scores and the LEIDS-rumination scores were added in two separate analyses to investigate which is better associated with relapse in this patient group receiving MBCT. In addition to the LEIDS-subscale, rumination was also measured with the Ruminative Response Scale (RRS; Nolen-Hoeksema, 1991). The brooding subscale has been shown to be associated with depressive symptoms, while the reflection subscale was not (Schoofs et al., 2010). Therefore, we did two separate analyses; one with the RRS-total and one with the RRS-brooding subscale. Self-compassion was measured with the Self Compassion Scale (SCS; Neff, 2003) and Mindfulness with the Five Facet Mindfulness Questionnaire (FFMQ; Baer et al., 2006).

2.6 Statistical analysis

We used Cox proportional hazards regression models to examine the associations of baseline CR (LEIDS-R), rumination (RRS), self-compassion (SCS), and mindfulness (FFMQ) scores with time to first relapse (primary endpoint). Patients dropping out during follow-up or without a relapse within 15 months were considered censored. Well-established factors associated with relapse, that is, residual depressive symptoms at baseline (IDS-C) and number of previous depressive episodes (log-transformed), were a-priori included as covariates in all Cox-analyses (Hardeveld et al., 2010).

Because compliance to discontinuation and maintenance of mADM was variable, we added ADM discontinuation as time-dependent covariate to the model (i.e., using the timepoint during follow-up where the patient actually discontinued mADM).

First, for each factor of interest (i.e., LEIDS-R, RRS, SCS, and FFMQ), we applied a multivariate model including the factor of interest, IDS-score, number of previous depressive episodes, mADM-use, and the interaction of the factor of interest with mADM-use. The multivariate models were then pruned by stepwise eliminating the nonsignificant variables/interactions (p ≥ .050) to obtain the most parsimonious model. We assessed the optimal association between these models with the Akaike Information Criterion (AIC). Second, we combined all significant factors of interest, assessed with the analysis above, in a multivariate model. Because our factors of interest are continuous variables, the hazard ratio (HR) indicates the change in the risk of relapse if the score of the questionnaire rises by one unit. To show the clinical significance of our factors of interest, we summarized relapse risks stratified for incremental levels of these factors, numbers of episodes, residual symptoms, and mADM-use in Supporting Information Risk Tables (using logistic regression models). Eighty-five participants dropped out or relapsed before finishing the first 3 months (i.e., the MBCT-period). We therefore performed a sensitivity analysis by using baseline scores in the group that completed the first three months.

3 RESULTS 3.1 Demographics and clinical characteristics

We included 282 participants. Twenty-two patients were excluded; 19 due to missing baseline scores, 1 due to an unknown ADM discontinuation date, and 1 because of a relapse 10 weeks before starting MBCT, leaving 260 patients for analysis. There were several significant differences in clinical characteristics between the two as received intervention groups (Table 1). Patients in the MBCT/mADM-discontinuation group were more often female, employed, and in full remission compared to patients in the MBCT/mADM group (all p ≤ .046), indicating that at the start of the study, participants in the MBCT/mADM-discontinuation group appeared more clinically stable than in the MBCT/mADM group. There were no significant differences in factors of interest between the two groups.

Table 1. Characteristics of patients with recurrent depression who were offered MBCT + mADM or MBCT with mADM discontinuation (as received), including patients from two trials and excluding those with missing baseline data, missing data on discontinuation, and one incorrectly randomized patient MBCT/mADM (n = 183) MBCT/ADM discontinuation (n = 77) All subjects (n = 260) pa N (%) N (%) N (%) Female 117 (63.9) 59 (76.6) 176 (67.7) .046 Educational level .566 Low 12 (6.7) 8 (10.5) 20 (7.9) Middle 48 (27.0) 21 (27.6) 69 (27.2) High 118 (66.3) 47 (61.8) 165 (65.0) Marital status .851 Single 45 (25.0) 17 (22.4) 62 (24.2) Married/cohabiting 106 (58.9) 45 (59.2) 151 (59.0) Divorced/widowed 29 (16.1) 14 (18.4) 43 (16.8) Employed 108 (59.0) 59 (76.6) 167 (64.2) .007 Remission .040 Full, IDS-C ≤ 11 91 (49.7) 49 (63.6) 140 (53.8) Partial, IDS-C > 11 92 (50.3) 28 (36.4) 120 (46.2) Type of mADM .573 SSRI 135 (73.8) 60 (77.9) 195 (75.0) TCA 36 (19.7) 11 (14.3) 47 (18.1) Other 12 (6.6) 6 (7.8) 18 (6.9) Previous CBT treatment 112 (61.2) 39 (50.6) 151 (58.1) .115 Suicide attempts 31 (16.9) 18 (23.4) 49 (18.8) .226 Relapse 71 (38.8) 49 (63.6) 120 (46.2) .000 Mean (SD) Mean (SD) Mean (SD) pa Age 50.5 (11.3) 49.7 (10.9) 50.3 (11.1) .605 IDS-C (baseline)b 12.0 (15.0) 9.0 (10.0) 10.0 (14.0) .068 Nr. previous episodesb 5.0 (4.0) 4.0 (3.0) 4.0 (3.0) .197 Age of MDD onsetb 22.0 (14.0) 25.0 (16.0) 23.0 (15.0) .187 LEIDS-R (baseline) 77.8 (14.1) 76.7 (16.8) 77.4 (14.9) .647 LEIDS-R-Rumination (baseline)b 18.0 (6.0) 18.0 (6.0) 18.0 (6.0) .470 RRS (baseline) 48.1 (10.4) 47.6 (12.9) 47.9 (11.2) −695 RRS-Brooding (baseline)b 11.0 (4.0) 11.0 (5.0) 11.0 (4.0) .543 SCS (baseline) 86.2 (14.7) 87.7 (14.5) 86.7 (14.6) −491 FFMQ (baseline) 116.6 (16.6) 117.0 (15.2) 116.7 (16.2) −874 Abbreviations: CBT, cognitive-behavioral therapy; FFMQ, Five Facet Mindfulness Questionnaire; IDS-C, Inventory of Depressive Symptomatology – Clinician rated; LEIDS-R, Leiden Index of Depression Sensitivity-Revised; mADM, maintenance antidepressant medication; MBCT, mindfulness-based cognitive therapy; MDD, major depressive disorder; RRS, Ruminative Response Scale; SCS, Self-Compassion Scale; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. aDifference Event/Stop before finishing MBCT versus Event/Stop after finishing MBCT. bDue to skewed distribution medians and 25%–75% interquartile range are reported and a nonparametric test (Mann–Whitney U) was used.

Eighty-five of 260 participants (32.7%) dropped out or relapsed before the 3-month measurement. As a group, patients who had a relapse or dropped out early were more often in partial (rather than full) remission, had a lower age and age of onset of MDD, scored higher on CR and rumination, and lower on mindfulness (all p ≤ .038; Table S2). Thus, patients who dropped out or experienced a relapse before the 3-month measurement were more severely affected than patients who did not.

3.2 Association with future relapse

Table 2 presents the most parsimonious models with CR, rumination, self-compassion, or mindfulness as factors of interest. Residual symptoms and (discontinuation of) mADM-use were associated with relapse in all models (all p ≤ .031). After discontinuation of mADM, the relapse rate was 1.6–1.7 times greater compared to continuing mADM. The number of previous episodes was only associated with relapse in the self-compassion and mindfulness models (p = .045 and p = .032, respectively).

Table 2. Models including cognitive reactivity, rumination, self-compassion, or mindfulness with mADM discontinuation as time-dependent covariate (n = 260) Model HR 95% CI p AIC (BIC)b 1.1 Cognitive reactivity (LEIDS-R) 1185.211 (1199.438) Cognitive reactivity (LEIDS-R) 1.019 1.007–1.030 .002 Residual symptoms 1.019 1.002–1.036 .027 Episodes in historyc 1.676 0.789–3.561 .179 mADM-use (mADM vs. mADM discontinuation) 1.650 1.073–2.538 .023 1.2 Rumination (subscale LEIDS-R) 1195.444 (1209.687) Rumination (subscale LEIDS-R) 1.068 1.023–1.114 .003 Residual symptoms 1.021 1.004–1.038 .013 Episodes in historyc 1.934 0.942–3.974 .073 mADM-use (mADM vs. mADM discontinuation) 1.669 1.086–2.567 .020 2.1 Rumination (RRS) 1194.321 (1212.124) Rumination (RRS) 1.006 0.987–1.026 .525 Residual symptoms 1.026 1.009–1.043 .002 Episodes in historyc 1.736 0.842–3.580 .135 mADM-use (mADM vs. mADM discontinuation) 0.152 0.022–1.063 .058 Rumination (RRS)*mADM-use 1.052 1.012–1.093 .010 2.2 Rumination (subscale brooding) 1203.004 (1217.247) Rumination (subscale brooding) 1.036 0.977–1.098 .283 Residual symptoms 1.024 1.007–1.041 .005 Episodes in historyc 1.924 0.943–3.928 .072 mADM-use (mADM vs. mADM discontinuation) 1.659 1.074–2.563 .023 3 Self-compassion (SCS) 1188.607 (1202.803) Self-compassion (SCS) 0.992 0.980–1.005 .229 Residual symptoms 1.023 1.006–1.040 .008 Episodes in historyc 2.070 1.018–4.211 .045 mADM-use (mADM vs. mADM discontinuation) 1.630 1.057–2.514 .027 4 Mindfulness (FFMQ) 1184.527 (1198.723) Mindfulness (FFMQ) 0.985 0.973–0.998 .020 Residual symptoms 1.019 1.002–1.036 .028 Episodes in historyc 2.181 1.071–4.443 .032 mADM-use (mADM vs. mADM discontinuation) 1.608 1.044–2.478 .031 Abbreviations: FFMQ, Five Facet Mindfulness Questionnaire; LEIDS-R, Leiden Index of Depression Sensitivity-Revised; mADM, maintenance Antidepressant Medication; RRS, Ruminative Response Scale; SCS, Self-Compassion Scale. aDue to missing values for individual questionnaires the N is slightly different for different models. bAIC was also calculated with an equal number of participants (n = 256) for each predictor which shows that rumination (RRS) had the lowest AIC (AIC = 1170.030) followed by cognitive reactivity (AIC = 1171.159). cDue to a skewed distribution LOG transformation was used.

The significant association of relapse with CR, measured by LEIDS-R (HR = 1.019 [95% confidence interval (95% CI) = 1.007–1.030]), was independent of mADM-use (HR = 1.650 [1.073–2.538]) and did not change when mADM was used or not (i.e., no significant mADM-use*CR-interaction (p = .177)). Every 10-point increase in LEIDS-R resulted in approximately a 20.7% increase in relapse rate, with residual symptoms and mADM-use as independent factors associated with relapse in this model (Tables S3.1–S3.2).

For rumination measured by the LEIDS-R-subscale, we also found a significant association with relapse (HR = 1.068 [1.023–1.114]) although the AIC was slightly worse compared to the model with the full LEIDS-R. For rumination as measured by the RRS, we found an additional interaction between RRS-score and mADM-use (p = .010). This interaction indicated that rumination (RRS-scores) was especially associated with relapse in patients who discontinued mADM, while this effect was absent if patients continued mADM (Figure 1 and Tables S3.3–S3.4). When we confined the RRS-score to the brooding subscale, this interaction became nonsignificant, with higher AIC; that is, a worse model.

Graphical representation of interaction between rumination and antidepressant medication usage This graphical representation is based on a logistic regression model in which relapse anywhere within the 15-month follow-up was added as dependant variable. The median of residual symptoms (10) and episodes in history (4) of our sample where used for this representation. Odds ratios for independent variables included in the model were: IDS 1.034 (p = .017), episodes in history 3.019 (p = .050), mADM-usage 0.069 (p = .042), RRS 0.987 (p = .414), and RRS*mADM-usage interaction 1.087 (p = .003)

Mindfulness was significantly associated with relapse (p = .020). Every 10-point increase in FFMQ resulted in approximately a 14.0% decrease in risk of relapse (HR = 0.985 [0.973–0.998]). This was independent of residual symptoms, previous episodes, and mADM-use (Tables S3.5–S3.6). Self-compassion was not associated with relapse (p = .229).

Table S4 shows correlations between the variables of interest. Baseline LEIDS-R, RRS, SCS, and FFMQ were correlated. However, only the subscales relative to their full scale (LEIDS/RRS) and the SCS relative to FFMQ were highly correlated (>0.5). Finally, we included CR, RRS, and mindfulness scores in one model (Table 3). This model had the lowest AIC (1168.971). Only residual symptoms and mADM-use*RRS-interaction remained significant in this combined model (p = .032 and p = .029, respectively); CR, mindfulness, and mADM-use were no longer significantly associated with relapse (p ≥ .111). When the subscale brooding was added instead of the total RRS-score (Table 3), the AIC of this model was higher compared to the model with the total RRS scale (ΔAIC = 3.046). Moreover, the mADM-use*RRS-brooding-interaction was nonsignificant and discarded from the model. In the remaining model, thus without mADM-use*RRS-brooding-interaction, CR and mADM discontinuation became significantly associated with relapse (p = .009 and p = .031, respectively); all other variables were nonsignificant (p ≥ .073).

Table 3. Time-dependent Cox model with all significant factors of interest combined in one model (n = 256) Model HR 95% CI p AIC (BIC)