Introduction: Different psychotherapeutic interventions for late-life depression (LLD) have been proposed, but their evaluation in large, multicenter trials is rare. Objective: The present study evaluated the efficacy of a specific cognitive behavioral therapy (CBT) for LLD (LLD-CBT) in comparison with a supportive unspecific intervention (SUI), both administered in a specialist psychiatric outpatient setting. Methods: In this randomized, controlled, parallel group trial, we recruited participants (≥60 years) with moderate to severe depression at 7 trial sites in Germany. Participants were randomly assigned to the LLD-CBT or SUI group. The primary outcome was depression severity at the end of treatment measured by change on the Geriatric Depression Scale (GDS). Secondary outcomes included change in observer-rated depression, anxiety, sleep ratings, and quality of life throughout the treatment phase and at 6-month follow-up. Results: Between October 1, 2018, and November 11, 2020, we randomly assigned 251 patients to either LLD-CBT (n = 126) or SUI (n = 125), of whom 229 provided primary-outcome data. There was no significant between-group difference in the change in GDS scores at the end of treatment (estimated marginal mean difference: −1.01 [95% CI: −2.88 to 0.86]; p = 0.287). Secondary analyses showed significant improvements in several outcomes after 8 weeks and at follow-up in both treatment arms. Conclusions: Our data suggest that LLD-specific CBT and a supportive unspecific treatment both provide clinical benefit in patients with moderate to severe LLD without evidence for superiority of LLD-CBT.

© 2023 The Author(s). Published by S. Karger AG, Basel

Introduction

Late-life depression (LLD) can be defined as a depressive episode occurring after the age of 60 years. Meta-analyses observed a prevalence rate of 17.1% of clinically relevant depressive symptoms in this age-group [1]. LLD accounts for 5.7% of years lived with disability among the population over 60 years [2]. It is associated with reduced quality of life (QoL), increased suicide rates, negative impact on several diseases, increased mortality, and increased risk for all-cause dementia [3–5].

LLD is often not recognized or misdiagnosed and insufficiently treated [6, 7]. Compared with depression in early and mid-adulthood, treatment options of LLD are often less effective. Meta-analyses have shown that the number needed to treat for remission by antidepressant medication is around 7 in patients younger than 65 years and increases to 14.4 in adults older than 65 years [8–11]. In addition, intolerability and contraindications of antidepressants increase with age, and higher rates of adverse effects limit their application. A more recent network meta-analysis concluded that there is evidence for the efficacy of pharmacological treatment in LLD, but given the limited data, the findings cannot be considered robust [12]. Compared with pharmacological treatment, psychotherapy is better tolerated and provides potential benefit in LLD [11]. Cognitive behavioral therapy (CBT) is an established and effective type of psychotherapy for depression in younger adults [13]. The application of CBT in LLD is less well studied. The majority of CBT trials in LLD are either of limited sample size, single-center studies, or recruited participants through primary care or as self-referrals, which limits the generalizability to clinical populations with moderate to severe LLD in the psychiatric care setting [14–17]. In the abovementioned recent network meta-analysis on treatments of LLD, which included only trials with patients with operationalized major depressive disorder (MDD) diagnosis, a randomized design and without a high risk of bias, only one single-center 3-arm CBT study with 204 patients in total recruited through primary care was included [12]. This trial showed a significant effect of CBT on symptoms of depression in comparison with two control conditions [18].

A confirmatory trial testing the efficacy of age-specific CBT in a psychiatry-based multicenter setting in patients with moderate to severe LLD is missing. Importantly, CBT protocols for LLD need to be adapted to the specific needs and topics of patients at higher age, which are in part distinct from younger adults, including loss of significant others, retirement, physical impairment, and closeness to end of life among others. In a single-center pilot study, one author (M.H.) investigated the short- and long-term outcomes of a manualized 15-session CBT, specifically designed for patients with LLD (LLD-CBT), in comparison to a manualized supportive unspecific intervention (SUI), delivered in an individual or group setting. Both interventions reduced depressive symptoms significantly over a follow-up period of 1 year, and LLD-specific CBT reduced depressive symptoms more than SUI, specifically in the individual setting [19]. In the present randomized trial, we aimed to confirm the superior efficacy of LLD-CBT in comparison to SUI for moderate to severe LLD in a large sample in a multicenter setting.

Materials and MethodsStudy Design and Participants

We recruited 251 patients with LLD at 7 trial sites in Germany, which were either psychiatric university hospitals or psychotherapeutic university centers. Eligible participants were aged ≥60 years, outpatients, and met diagnostic criteria for moderate to severe MDD assessed by trained raters using the validated standard clinical Mini International Neuropsychiatric Interview for DSM-5 (M.I.N.I. Version 7.0.2). We included participants with a Geriatric Depression Scale (GDS) score >10, Quick Inventory of Depressive Symptomatology – Clinician Rating (QIDS-C) score >10, and Mini-Mental Status Test (MMST) score >25. We excluded individuals with bipolar depression, schizophrenia or other psychotic disorders, substance abuse or addiction, and dementia as well as with anxiety disorder or obsessive-compulsive disorder as stand-alone diagnoses. Acute suicidality or a high likelihood of prospectively regular use of benzodiazepines during the 8-week treatment period was an additional exclusion criterion. Patients with any planned psychotherapeutic treatment outside of the study or planned brain stimulation throughout the 8-week treatment period were excluded. Severe or instable medical conditions clearly impacting on depression or patients with a brain disease with relevant functional impairment (e.g., aphasia, Parkinson’s disease) were excluded. In case of existing pharmacological treatment, the antidepressive medication had to be stable for at least 6 weeks prior to baseline and had to remain stable during the 8-week treatment period. All participants provided written informed consent prior to all study procedures. The study was approved by the Institutional Review Board/Institutional Ethical Committee (IRB/IEC) of the University of Cologne and by all other local IRBs/IECs at the participating sites prior to initiation of the trial. The study protocol has been published previously [20]. The trial is registered at ClinicalTrials.gov (NCT03735576) and DRKS (DRKS00013769).

Randomization and Masking

Subjects were randomly assigned to one of two treatment arms (1:1 randomization) by a designated on-site researcher or trial manager, respectively, using the central 24–7 web-based internet randomization service ALEA, maintained by the Institute of Medical Statistics and Computational Biology (IMSB) at the University of Cologne. Randomization to the treatment arms was performed as stratified block randomization. The allocation sequence was derived from permuted blocks of varying length, in which block size was unknown to the investigators. The randomization was stratified by the trial site to prevent unbalanced allocation of the interventions to sites. The study was a single-blind (observer-blinded) trial. As such, all clinical interviews and outcome assessments were conducted by raters, who were blinded to the treatment arm allocation. The raters were centrally trained, certified, and supervised in the assessment of all outcomes. The sites implemented procedures to maintain rater blinding to the treatment assignment by informing and reminding patients at each visit, not to mention their treatment condition or content to the rater, and by locating the rater and the study therapists as well as documentation at different physical locations. Therapists refrained from any conversation about any aspects of individual treatments with the raters.

Procedures

The sequence of clinical assessments was standardized across all sites using uniform, manualized procedures. The first visit of the study was a screening and baseline (T0) visit, at which informed consent was obtained; the M.I.N.I. interview was conducted to establish the diagnosis of MDD, and the inclusion and exclusion criteria as well as the primary outcome were assessed. In those subjects who passed the screening procedure, the secondary outcomes were obtained. After the baseline assessment, subjects were randomized to either of the two treatment arms. In week 5 after randomization and 50% of the treatment session, the primary and secondary outcomes were assessed (T1). End-of-treatment primary and secondary outcomes were obtained in week 10 (T2). The final follow-up assessment (T3) was performed 6 months after randomization.

The interventions included 8 weeks of manual-based, individual, 15-session, twice weekly, outpatient treatment in each arm of the trial (LLD-CBT, SUI). Both are described in detail in the online supplementary 2 (for all online suppl. material, see www.karger.com/doi/10.1159/000529445) and have been published previously [21]. All therapists were fully licensed in CBT and had several years of clinical experience. All were trained in both interventions and delivered either one according to individual randomization in order to avoid systematic therapist bias. All were obliged to adhere to the respective manuals in each individual therapy session. Adherence was assured by bimonthly continuous central supervision of all therapists provided by M.H. and by supervision by trained local therapy experts. In addition, all therapy sessions were recorded on film. Central assessment of adherence with a structured adherence scale was performed on randomly selected recordings. The assessment of treatment adherence by trained raters is described in the online supplementary 2.

Outcomes

The primary outcome was defined a priori as the change in the GDS score from baseline to end of treatment and was calculated by subtracting the GDS score at baseline from the GDS score at end of treatment. We used the 30-item GDS version (range 0–30, higher scores indicating more severe symptoms), a widely established, self-report measure of depressive symptoms in older subjects, used in clinical trials [16].

Secondary outcome measures included the Quick-Inventory of Depressive Symptomatology Clinician-Rated Version (QIDS-C), a 16-item clinician rating to measure the severity of MDD symptoms according to DSM-IV [22]. In addition, we applied the German translation of a depression-specific patient-reported outcome questionnaire (Patient-Reported Outcome in Major Depressive Disorder [PRO-MDD]) [23]. We assessed anxiety symptoms with the 20-item Geriatric Anxiety Inventory (GAI) as a self-report measure [24]. To assess subjective QoL, the World Health Organization Quality of Life Assessment (WHOQOL-BREF) was used which consists of the following domains: physical and psychological aspects of QoL, social relationships, environmental aspects, and overall QoL. For assessing specific aspects of QoL at higher age, this instrument was complemented by the 24-item add-on module WHOQOL-OLD [25]. In addition, physical and mental health-related QoL were measured with the 36-item Short-Form Health Survey (SF-36) [26]. Sleep disturbances and disruption of circadian rhythms were assessed with the self-report questionnaires Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS), and Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire (RBDSQ).

The study protocol (online suppl. 1) included additional assessments, which will be analyzed and presented in subsequent reports. These comprised an extended cognitive assessment at baseline and follow-up, an assessment of the continuous longitudinal course of depressive symptoms over time at follow-up, and a process evaluation of patient satisfaction at the end of treatment [20]. Childhood trauma and personality traits were assessed at baseline to investigate mediator and moderator hypotheses on treatment outcomes. These findings will also be reported later.

Adverse and serious adverse events (AEs/SAEs) were recorded for the entire treatment duration and the 6-month follow-up period and were reported to the project’s Data Safety and Monitoring Board (DSMB). SAEs were reported also to each IRB/IEC. We defined an SAE as any medical event that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, was any other important medical condition that might require medical or surgical intervention to prevent one of the outcomes listed. We also included suicide attempts as an SAE. An AE was defined as any unfavorable and unintended sign, symptom, or disease, whether or not considered to be related to the treatment. This included worsening of symptoms, occurrence of new symptoms, occurrence of passive suicidal thoughts, active suicidal intentions or plans, problems in the patient-therapist relationship, private problems, occupational problems, or other medical conditions (e.g., influenza, fractures, etc.). We recorded reports of suicidal ideations and their relationship to treatment at every visit. Participants were specifically asked about illnesses and hospital admissions at the visits. After the onset of the SARS-CoV-2 pandemic in spring 2020, all participants were asked about a COVID-19 infection.

Statistical Analysis

The sample size and power calculations have been described previously [20] and are reported in the online supplementary 1. The power calculation was based on the results of the pilot trial [19]. Briefly, the current trial was powered to detect a difference of 2.5 GDS points in the change between baseline and end of treatment between both arms (d = 0.4). We calculated that the two-sample t test required 99 subjects per group to detect such a difference with 80% power at a two-sided significance level of p < 0.05. Accounting for up to 20% attrition, 248 subjects in total (124 per group) were calculated to be required. The applied mixed model for repeated measures (MMRM) approach with adjustment for baseline variables is likely to increase the statistical power further compared with a two-sample t test. The analyses followed the pre-specified statistical analysis plan (SAP, online suppl. 1). All analyses were performed with SPSS Statistics (IBM Corp., Armonk, NY, USA). Descriptive statistics summarizing all variables and outcome measures at all timepoints are reported by the treatment group and across the total sample. The primary full analysis set is derived from the intention-to-treat (ITT) population (all subjects randomized with a valid baseline assessment and at least one valid follow-up outcome assessment). The primary outcome was evaluated by an MMRM with the fixed effects of the baseline GDS score, therapist, treatment group, visit and the interaction treatment group*visit (ARH1-structured covariance matrix over time) with corresponding marginal means and contrast tests. We calculated a between-group effect size by dividing the difference of the mean change in GDS (end of treatment minus baseline) of the groups by the pooled standard deviation (SD). In addition to the analyses in the statistical analysis plan, we calculated remission (≤10 points on the GDS at end of treatment) and response rates (all remitted patients and patients with a reduction of 50% of the baseline GDS score at the end of treatment) and compared them between groups with Pearson’s χ2 test.

Secondary outcomes, including all other clinical measures as well as the GDS differences at 6-month follow-up, were analyzed along the same lines. In addition, we investigated the change in primary and secondary outcome measures from baseline to week 5, end of treatment, and follow-up for LLD-CBT and SUI groups separately. We calculated effect sizes (Cohen’s d) for the LLD-CBT and SUI groups separately by dividing the difference from the GDS scores at end of treatment to baseline by the SD of the baseline GDS score. Subgroup analyses were done by baseline severity of depression (moderate: GDS score <20, severe: GDS score ≥20), trial site, and sex with interaction analysis of sex, site, and depression severity.

Analysis of the set of subjects treated and observed per protocol (PP) defined as all subjects without major protocol violations and at least 9 sessions in one of the interventions and all outcome assessments were analyzed along the same lines as the ITT population. Time-to-event (dropout) distributions of dropouts were summarized by the Kaplan-Meier method and compared by the (stratified) log-rank test. All results are reported uncorrected for multiple comparison. As such, in the primary end point analysis, the difference of the GDS change between both treatment arms in the ITT population is considered confirmatory.

All safety parameters (AE, SAE) were analyzed by subject, treatment group, category, seriousness, severity, and relatedness to treatment. The analyses were performed for the safety population and stratified by treatment group.

Results

Between October 1, 2018, and November 11, 2020, we screened 299 participants for the study and randomly assigned 251 patients to either the LLD-CBT (n = 126) or SUI (n = 125) group (shown in Fig. 1). Recruitment by site is shown in online supplementary Table S2 in Supplement 2. The ITT population comprised 229 participants (91.2%), including 115 of 126 (91.3%) of the LLD-CBT and 114 of 125 (91.2%) of the SUI group. 213 of 251 participants (84.9%) fulfilled the criteria of the PP population, including 105 of 126 (83.3%) in the LLD-CBT group compared with 108 of 125 (86.4%) in the SUI group. There was no significant difference in dropout rates between groups (online suppl. Table S8–9 in Suppl. 2).

Fig. 1.

Trial flowchart. LLD-CBT, cognitive behavioral therapy for late-life depression; SUI, supportive unspecific intervention.

Demographic data for the participants in the ITT population are shown in Table 1. Patient characteristics at baseline were balanced between groups (Table 1). The mean age across both groups was 70.2 years (SD 7.1). Most participants were women and not employed or retired. Fifty two percentage were without spouse. The participants were all outpatients, and all resided independently at home either alone, with their spouse, or other family members (siblings, children). None of the patients lived in a nursing care or assisted living. The mean age at onset of the first depressive episode was 42.6 (median 42 years; IQR 25–59). Seventy six percent of patients had their first depressive episode before 60 years of age. The mean number of lifetime depressive episodes without the current was 4.4 (SD 9.8; range 0–99). The median duration of the current depressive episode was 1.15 years. The mean number of antidepressants taken over lifetime was 1.8 (SD 2.2; range 0–10).

Table 1.

Baseline demographic and clinical characteristics of the ITT population.

LLD-CBT (n = 115)SUI (n = 114)Overall (n = 229)Age, years Mean (SD)69.6 (7.3)70.7 (6.9)70.2 (7.1) Median (IQR; range)68 (64–74; 60–92)70 (65–77; 60–87)69 (64–75; 60–92)Gender, n (%) Female83 (72)68 (60)151 (66) Male32 (28)46 (40)78 (34)Relationship status, n (%) Single, separated, or widowed59 (51)60 (53)119 (52) Married or with partner56 (49)54 (47)110 (48)Living alone, n (%)51 (44)49 (43)100 (44)Years of education Mean (SD)14.7 (2.7)14.8 (3.7)14.8 (3.2) Median (IQR; range)15 (12–17; 8–20)15 (12–17; 8–36)15 (12–17; 8–36)Employment, n (%) Currently employed25 (22)26 (23)51 (22) Unemployed or retired90 (78)88 (77)178 (78)Age at the first depressive episode Mean (SD)43.4 (21.4)41.8 (19.7)42.6 (20.6) Median (IQR; range)45 (23–61; 4–85)40 (25–58; 5–82)42 (25–59; 4–85)First depressive episode <60 years of age, n (%) Yes83 (72.8)85 (79.4)168 (76) No31 (27.2)22 (20.6)53 (24)Number of depressive episodes* Mean (SD)3.9 (8.3)5.0 (11.2)4.4 (9.8) Median (IQR; range)2 (1–3; 0–50)2 (1–5; 0–99)2 (1–4; 0–99)Duration of the current depressive episode (weeks, patient-reported) Mean (SD)181.7 (421.0)135.6 (226.1)158.8(338.3) Median (IQR; range)64 (30–150; 3–3922)52 (24.5–132.5; 2–1560)60 (26–150; 2–3922)Inpatient psychiatric treatment (lifetime), n (%)44 (38)46 (40)90 (39)Outpatient psychiatric treatment (lifetime), n (%)80 (70)80 (70)160 (70)Outpatient psychotherapy (lifetime), n (%)79 (69)75 (66)154 (67)Antidepressant medication in the past, n (%) Yes78 (69.6)70 (66)148 (67.9) No34 (30.4)36 (34)70 (32.1)Number of antidepressants in the past Mean (SD)1.7 (2.2)1.8 (2.2)1.8 (2.2) Median (IQR, range)1 (0–2; 0–10)1 (0–3; 0–10)1 (0–2; 0–10)Suicide attempts (lifetime), n (%)6 (5)16 (14)22 (10)Current outpatient psychiatric treatment, n (%)51 (44)52 (46)103 (45)Current use of psychopharmacological drugs (regular; patient-reported), n (%)51 (44)51 (45)102 (45)GDS, 30-item version score (possible range: 0–30)21.0 (4.3)20.4 (4.2)20.7 (4.3)

Participants received a mean of 13.3 LLD-CBT sessions (SD 2.8) or 13.6 SUI sessions (SD 2.4) in the ITT population. In the PP population, participants received a mean of 14.1 LLD-CBT sessions (SD 1.6) or 14.0 SUI sessions (SD 1.6). Ratings of the delivered therapy sessions showed very good adherence to therapy manuals in both treatment arms (online suppl. 2).

Primary-Outcome Analysis

At baseline, the mean GDS score was 21.0 (SD 4.3) in the LLD-CBT arm and 20.4 (SD 4.2) in the SUI arm. A mean score of 13.5 (SD 7.6) was observed in the LLD-CBT arm and 14.2 (SD 6.9) in the SUI arm at the end of treatment (shown in Fig. 2; Table 2). There was no significant between-group difference in the change in GDS scores from baseline to the end of treatment (estimated marginal mean difference: −1.01 [95% CI: −2.88 to 0.86]; p = 0.287). The nonsignificant effect size difference of the two treatment groups was d = 0.18 (95% CI: −0.09 to 0.44), favoring the LLD-CBT group.

Fig. 2.

Primary outcome (Geriatric Depression Scale, GDS) over the course of the study. The two treatment arms did not differ at the end of treatment. Error bars show the SD. LLD-CBT, cognitive behavioral therapy for late-life depression; SUI, supportive unspecific intervention.

Table 2.

Comparison of outcome measures between the LLD-CBT and SUI groups (ITT population)

LLD-CBTSUIEstimated marginal mean difference (95% CI)p valueCohen dNo.score, mean (SD)No.score, mean (SD)Primary outcome GDS score (possible range: 0–30)  Baseline11521.0 (4.3)11420.4 (4.2)  Intermediate (week 5)11215.6 (6.6)11316.9 (5.4)−1.59 (−3.03 to −0.15)0.030*  End of treatment (week 10)10913.5 (7.6)11014.2 (6.9)−1.01 (−2.88 to 0.86)0.2870.18  Follow-up (month 6)10114.0 (7.4)10514.9 (6.6)−0.95 (−2.85 to 0.94)0.323Secondary outcomes QIDS-C score (possible range: 0–27)  Baseline11514.3 (2.3)11414.4 (2.5)  Intermediate (week 5)1128.8 (4.4)1139.5 (4.2)−0.82 (−1.83 to 0.196)0.114  End of treatment (week 10)1107.5 (4.9)1107.6 (4.7)−0.23 (−1.45 to 0.996)0.7160.029  Follow-up (month 6)1017.5 (5.4)1048.3 (4.6)−0.73 (−2.11 to 0.65)0.297 GAI score (possible range: 0–20)  Baseline11311.2 (4.3)11111.9 (4.2)  Intermediate (week 5)1099.0 (5.2)11110.3 (4.6)−0.81 (−1.84 to 0.23)0.128  End of treatment (week 10)1068.2 (5.4)1069.0 (5.2)−0.12 (−1.26 to 1.03)0.839  Follow-up (month 6)977.4 (5.2)998.6 (5.2)−0.72 (−1.99 to 0.54)0.261 PRO-MDD score (possible range: 0–350)  Baseline113142.1 (52.5)112139.3 (51.0)  Intermediate (week 5)108115.4 (62.1)111121.8 (53.0)−6.76(−18.86 to 5.34)0.272  End of treatment (week 10)106103.4 (64.0)106105.3 (55.6)−1.95 (−16.41 to 12.52)0.791  Follow-up (month 6)97103.1 (63.5)99111.6 (55.9)−9.28 (−25.08 to 6.51)0.248 WHOQOL-BREF total score (possible range: 0–100)  Baseline11243.0 (18.2)11139.6 (16.8)  Intermediate (week 5)10756.4 (20.2)11157.4 (16.5)−3.57 (−7.96 to 0.82)0.110  End of treatment (week 10)10457.7 (20.5)10557.7 (19.6)−1.91 (−6.1 to 3.096)0.453  Follow-up (month 6)9659.0 (20.3)9759.8 (17.1)−2.61 (−7.53 to 2.31)0.297 WHOQOL-OLD total score (possible range: 0–100)  Baseline11255.3 (11.5)11253.7 (11.7)  Intermediate (week 5)10457.7 (13.5)11155.2 (12.2)0.95 (−1.02 to 2.93)0.343  End of treatment (week 10)10660.5 (13.6)10657.5 (11.9)1.65 (−0.797 to 4.09)0.185  Follow-up (month 6)9460.5 (13.6)9858.7 (12.1)1.574 (−1.06 to 4.21)0.240 SF-36 physical health score (possible range: 0–100)  Baseline11144.4 (11.1)11043.1 (10.7)  Intermediate (week 5)10644.3 (10.2)10944.0 (10.6)−0.98 (−2.82 to 0.86)0.297  End of treatment (week 10)10544.3 (11.5)10343.6 (11.2)−0.44 (−2.53 to 1.64)0.675  Follow-up (month 6)9343.5 (10.1)9745.5 (10.5)−2.31 (−4.16 to −0.46)0.015* SF-36 mental health score (possible range: 0–100)  Baseline11132.0 (10.7)11031.9 (8.8)  Intermediate (week 5)10638.4 (13.3)10935.8 (9.6)2.05 (−0.64 to 4.73)0.134  End of treatment (week 10)10541.0 (13.1)10339.1 (12.0)1.84 (−1.32 to 4.99)0.252  Follow-up (month 6)9342.2 (13.1)9738.2 (11.6)4.09 (0.65–7.54)0.020* ISI score (possible range: 0–28)  Baseline11213.5 (6.1)11014.1 (6.0)  Intermediate (week 5)10811.9 (7.2)11112.4 (5.9)0.222 (−0.948 to 1.392)0.709  End of treatment (week 10)10610.9 (6.7)10610.8 (6.3)0.949 (−0.285 to 2.183)0.131  Follow-up (month 6)9710.3 (6.8)9810.8 (6.4)0.177 (−1.232 to 1.585)0.805 ESS score (possible range: 0–24)  Baseline1128.8 (4.5)1117.9 (4.7)  Intermediate (week 5)1078.7 (4.8)1108.1 (4.7)0.032 (−0.835 to 0.900)0.941  End of treatment (week 10)1068.0 (4.7)1067.0 (4.4)0.328 (−0.536 to 1.192)0.455  Follow-up (month 6)968.2 (4.8)986.9 (3.9)0.506 (−0.419 to 1.431)0.282 RBDSQ score (possible range: 0–13)  Baseline1134.0 (2.1)1134.5 (2.7)  Intermediate (week 5)1084.0 (2.5)1104.5 (2.7)−0.218 (−0.701 to 0.264)0.374  End of treatment (week 10)1063.6 (2.5)1064.1 (2.8)−0.155 (−0.655 to 0.344)0.541  Follow-up (month 6)953.6 (2.5)973.9 (2.7)0.145 (−0.357 to 0.647)0.568Additional Analyses of the GDS

Secondary analyses showed a significant reduction in GDS scores at the end of treatment compared to baseline in both groups (estimated marginal mean: −6.80 [95% CI: −8.17 to −5.44] in the LLD-CBT arm and −5.79 [95% CI: −7.18 to −4.40] in the SUI arm). The MMRM revealed a significant main effect for visit with a significant improvement of depressive symptoms over time (F = 22.238; p < 0.001) in both groups. The effect size estimates for the GDS reduction in single-group, pretest-posttest design was d = −1.75 (95% CI: −2.07 to −1.43) for the LLD-CBT arm and d = −1.47 (95% CI: −1.79 to −1.16) for the SUI arm. There was a significant between-group difference in the change in GDS scores at week 5 of treatment (estimated marginal mean difference: