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Randomisation and blinding
BLIND
Participants who met the specified inclusion and exclusion criteria were assigned to one of four groups (RT group, HMB group, combination group, or control group receiving standard care) in a 1:1:1:1 ratio using a computer-generated random sequence. To ensure allocation concealment, each centre prepared sequentially co...
PMC10724983
Intervention protocol
PMC10724983
Standard care
Participants in four groups received comprehensive rehabilitation and nutrition management, overseen by physicians and charge nurses. Early rehabilitation included activities such as passive joint mobilisation, passive sitting, bedside sitting, bicycle-assisted training, active bedside exercises, dynamic standing, assi...
PMC10724983
Resistance training (RT)
Administered, hip flexion
The intervention protocol encompassed three physical function levels: supine, sitting, and standing. Each level consisted of seven to eight actions, such as chest pressing, elbow flexion, rowing, ankle dorsiflexion, ankle plantarflexion, knee extension, hip flexion, bridge exercises, and abdominal breathing. These exer...
PMC10724983
HMB intervention
The nutritional supplement used in this study was JIROU (EnterNutr, Guangzhou), containing 8.32 g of maltodextrin, 1.5 g of HMBCa, 0.1 g of sweet orange powder, and 0.08 g of sucralose per 10 g. It provided 34 kcal of energy and no protein. The supplement, which included 1.5 g of HMB, was dissolved in 100 ml of warm wa...
PMC10724983
Data collection and outcome measures
Outcome assessors were trained and masked to group allocation. Outcome measurements in this study were divided into four categories, that is, physical function, muscle strength, body composition, and health-related quality of life.
PMC10724983
Physical function
(1) Short Physical Performance Battery (SPPB) was used to assess physical function, comprising a standing balance test, four-metre walking speed, and five sit-to-stand tests, each item worth 0–4 points, with a total score of 0–12 points [(2) 6-Minute Walk Test (6MWT) To evaluate functional endurance capacity and mobili...
PMC10724983
Muscle strength
ICU-AW
CONTRACTION
(1) The MRC score was used to assess the muscle strength of the six major muscle groups of the extremities. Each group is divided into six levels according to the Oxford muscle strength scale, with a total score of 0–60. Higher scores represent greater muscle strength. MRC is considered the gold standard for the diagno...
PMC10724983
Body composition
appendicular skeletal muscle mass
Bioelectrical impedance analysis (BIA, NUTRILAB, AKERN, Italy) was utilised to assess fat-free mass (FFM), appendicular skeletal muscle mass (ASMM), skeletal muscle index (SMI), and phase angle (PhA).
PMC10724983
Primary outcomes
SPPB and 6WMD were measured at hospital discharge.
PMC10724983
Secondary outcomes
ICU-AW
Assessments were conducted at each time point for body composition, MRC score, ICU-AW rate, grip strength, MMSE, HADS, SF-36, IES-R, and 60-day mortality, length of stay.
PMC10724983
Quality control
(1) A multicentre research team was established with sufficient personnel and reasonable hierarchy to ensure smooth project implementation. ICU nurse managers served as sub-centre leaders, while overall execution in each sub-centre was handled by head educators or quality control nurses from the respective departments....
PMC10724983
Statistical analysis
PMC10724983
Sample size determination
A pre-study power analysis conducted using G Power software estimated that approximately 24 patients per group (with a total of 96) were required to detect a 35% improvement in physical function between the control and treatment groups, with a power of 0.8 and an alpha level of 0.05.The data was processed using IBM SPS...
PMC10724983
General characteristics analysis
Normality of continuous variables was assessed using the SW-test, PP-plot, and QQ-plot. Normally distributed variables were described using mean and standard deviation, while non-normally distributed variables were described using median and interquartile range. Categorical variables were described using frequency and ...
PMC10724983
General linear mixed model
ICU-AW
SECONDARY, REGRESSION
The GLMM investigated discrepancies in SPPB and 6WMD at hospital discharge, as well as SF-36 and IESR scores at one month post-discharge. It also explored differences and trends in FFM, ASMM, SMI, and PhA among the four groups at various assessment time points: T0, T1w, T2w, and hospital discharge. Additionally, the GL...
PMC10724983
Results
PMC10724983
Patient characteristics
MODS, Comorbidity
MULTIPLE ORGAN DYSFUNCTION SYNDROME, MODS, CRITICALLY ILL
A total of 817 patients from 5 centres were initially assessed for study eligibility from July 2022 to December 2022. Among them, 699 were excluded due to not meeting the inclusion and exclusion criteria, while six declined to participate. Consequently, 112 patients were randomly allocated. Of these, eight patients wit...
PMC10724983
Delivery and adherence to the interventions
gastrointestinal reactions, gastrointestinal problems
The median duration of ICU stay prior to the study had no difference among four groups, as illustrated in Table The actual number of interventions conducted by the HMB group and the combination group were 22.0 and 18.0, with respective compliance rates of 91.22% and 92.03%, respectively. The cumulative number of incomp...
PMC10724983
Daily activity and energy intake
delirium, gastrointestinal reactions
PROTEIN DEFICIENCY
There were no statistically significant differences between the four groups in terms of gastrointestinal reactions, average daily sitting time, walking time, cumulative energy deficiency, cumulative protein deficiency, or delirium (The differences in daily profile among the four groups
PMC10724983
Primary outcomes
EVENT
GLMM analysis revealed significant differences between the four groups in terms of SPPB overall score, balance ability, four-metre gait speed score, and 6MWD (Results of GLLM analysis for comparison of SPPB/6MWD/SF-36/IESRSPPB: Short Physical Performance Battery; 6WMD: Six-Minute Walk Distance; SF-36: Short-Form-36 Hea...
PMC10724983
Secondary outcomes
PMC10724983
60-day mortality and length of stay
This study observed a 60-day mortality rate of 8.0%, with no cases in the RT group, and 10.7% (three cases) in each of the other three groups. The difference was not statistically significant (P > 0.05). Additionally, there were no significant differences (
PMC10724983
Body composition
The results of the GLMM analysis indicated there were no statistically significant differences (
PMC10724983
Health-related quality of life
There were no differences (
PMC10724983
Discussion
muscle mass, ICU-AW, critically ill, muscle wasting
DISEASE, CRITICALLY ILL, MUSCLE WASTING
Our findings indicate that RT improved physical function, muscle strength, and physical activity in MICU patients to a comparable extent to the combined intervention group. However, neither RT, HMB intervention, nor the combined intervention demonstrated efficacy in reducing muscle wasting or enhancing patients’ self-r...
PMC10724983
Conclusion
This novel multicentre four-arm RCT has shown that multilevel RT intervention, with or without HMB intervention throughout the entire hospitalisation period, seems to enhance the physical function and muscle strength of MICU patients. However, none of these treatments had a significant impact on body composition or qua...
PMC10724983
Acknowledgements
We would like to express our gratitude to the medical team in the multi-centre intensive care units for their assistance and professional advice during the implementation of this study.
PMC10724983
Author contributions
TTW and HL designed the study and drafted the manuscript; LLC provided statistical advice and support; QLC provided clinical expertise and advice; XXL, YNZ, XXC, CJL, MLX, YQW, JBW and JX were responsible for conducting intervention and developing the data collection, HL participated in the development of the ethical r...
PMC10724983
Funding
This study was supported by Fujian Provincial Department of Science and Technology's guiding projects, China (NO: 2021Y0051).
PMC10724983
Declarations
PMC10724983
Ethics approval and consent to participate
This study rigorously adheres to ethical principles and respects the preferences of all participants. Before the study is conducted, the study purpose, content, and procedure must be completely explained, informed consent must be signed, and notification must be done properly. Under no circumstances may the researcher ...
PMC10724983
Consent for publication
Not applicable.
PMC10724983
Availability of data and materials
The datasets generated and/or analysed during the proposed study will be available from the corresponding author upon reasonable request.
PMC10724983
Competing interests
The authors declare that they have no competing interests.
PMC10724983
References
PMC10724983
Background
trauma, depression, chronic depression, ill
Whether and how psychotherapies change brain structure and function is unknown. Its study is of great importance for contemporary psychotherapy, as it may lead to discovery of neurobiological mechanisms that predict and mediate lasting changes in psychotherapy, particularly in severely mentally ill patients, such as th...
PMC10652457
Methods/design
chronic major depression, trauma
Patients with chronic major depression and a history of early life trauma will be recruited, assessed, and treated across 3 international sites: Germany, Switzerland, and the United States. They will be randomized to one of two treatment arms: either (1) once weekly psychoanalytic psychotherapies, or (2) 3–4 times week...
PMC10652457
Discussion
depression, trauma
MODE may allow the identification of brain-based biomarkers that may be more sensitive than traditional behavioral and clinical measures in discriminating, predicting, and mediating treatment response. These findings could help to personalize care for patients who have chronic depression patients and early life trauma
PMC10652457
Supplementary Information
The online version contains supplementary material available at 10.1186/s12888-023-05287-6.
PMC10652457
Keywords
Open access funding provided by University of Lausanne
PMC10652457
Introduction
PMC10652457
Chronic depression and psychoanalytic psychotherapy research
depression, major depression, chronic depression, depressive symptoms
DISORDER, PAT
Chronic depression is a common disorder. Population lifetime prevalence estimates are 3–15% for major depression [Patients with chronic depression require tailored psychotherapeutic treatments that address their specific clinical needs [Only a small number of studies, however, have assessed the effectiveness of long-te...
PMC10652457
Early trauma, frequency of sessions, and treatment effects in chronic depression
chronic depression, depressed, traumatization, trauma
An unexpected, post hoc finding of the LAC study was that more than 80% of chronically depressed patients participating in the study suffered from early trauma, and that these patients responded especially well to high frequency psychoanalytic psychotherapy, often achieving sustained, structural changes in personality ...
PMC10652457
Psychotherapy research in depression using brain imaging
Several investigators have used brain imaging technologies to study the associations of psychotherapies with measures of brain structure and function [
PMC10652457
Objectives
depressive, depressed
Although considerable evidence supports the clinical effectiveness of psychoanalytic therapies, we do not yet understand the mechanisms through which they improve symptoms and reduce functional impairments – knowledge that can further enhance treatment effectiveness, especially in the highest risk and most complex clin...
PMC10652457
Specific aims and hypotheses
PMC10652457
AIM 1
depressed, trauma
Identify how long-term psychoanalytic therapies change brain structure and function in chronically depressed patients with a history of early trauma and to assess how those changes differ in patients assigned randomly to either high or low frequency weekly sessions.
PMC10652457
AIM 2
Assess whether these brain changes significantly mediate clinical improvement over 1 year of treatment.
PMC10652457
Primary hypotheses
High compared with low frequency treatment will normalize brain structure and function.
PMC10652457
Brain structure
depression
Based on prior findings in chronic depression patients in an RCT of medication therapy vs placebo [
PMC10652457
Brain activation
High compared with low frequency treatment will produce greater change in brain activity (a greater degree of normalization relative to healthy control values) in ventral medial brain regions during the functional MRI (fMRI) Cyberball paradigm for social exclusion, and the changes in brain activity will significantly m...
PMC10652457
Functional connectivity
depressed
High compared with low frequency treatment will produce a greater change in measures of functional brain connectivity after 1 year of treatment during resting state fMRI, particularly in the default mode network (DMN), which likely subserves the capacity for free association. Based on prior findings in chronically depr...
PMC10652457
Tissue microstructure
High compared with low frequency treatment will produce a more pronounced normalization of indices of tissue microstructure in white matter (increasing fractional anisotropy and decreasing mean diffusivity) measured with diffusion tensor imaging (DTI).
PMC10652457
Secondary hypotheses
PMC10652457
Psychopathology
depressive
Although high and low frequency treatments will both produce clinical improvement, improvement will be significantly greater for high frequency treatment in structural integration (measured with the Operationalized Psychodynamic Diagnosis Structure Questionnaire (OPD-SQ)), depressive symptoms (measured with the BDI-2),...
PMC10652457
Metabolic profile (only for a subgroup in Frankfurt)
Proton MR Spectroscopy (
PMC10652457
Methods/Design
PMC10652457
Study design
depressed
MODE is a randomized, parallel, superiority and single blinded controlled trial comparing the effectiveness of two active interventions – high frequency (Flow chart of the studyThis study design will overcome many of the limitations of prior psychotherapy effectiveness studies. It will include an active control conditi...
PMC10652457
Inclusion and exclusion criteria
PMC10652457
Patients
patients•, major depression, bipolar affective, schizoaffective, depressed, dysthymia, psychotic symptoms, depression, chronic depression, schizophrenic, trauma
SCID
Patients between 21 and 60 years of age of all genders suffering from chronic depression will be included in the study. Patients must be continuously depressed for more than one year and currently meet a diagnosis of major depression or dysthymia. The SCID interview will confirm a yearlong history of depression. Only p...
PMC10652457
Healthy control participants
depression, psychiatric, trauma
PHYSICAL ILLNESS
Inclusion criteria are: (1) no history of prior or current psychiatric diagnoses (Structured Clinical Interview for DSM-SCID); (2) no prior history of trauma on any of the CTQ subscales; (3) 21–60 years of age; and (4) sufficient knowledge of the local language to undergo assessments. Exclusion criteria are: (1) seriou...
PMC10652457
All participants
Standard MRI exclusion criteria will apply (metallic tattoos, pacemakers, or other metallic implants).
PMC10652457
Intervention and comparator
depressed
Study intervention will be comprised of low frequency psychoanalytic psychotherapy (1 session a week) for early traumatized, chronically depressed patients and high frequency psychoanalytic psychotherapy (3–4 weekly sessions). The active comparator condition, low frequency psychoanalysis, delivered by study therapists ...
PMC10652457
Primary outcomes: MRI brain measures
Assessment will comprise the following MRI brain measures. Anatomical MRI: measures of cortical thickness at all points across the cerebrum. Resting State Functional MRI (rsfMRI): measures of functional connectivity throughout the brain. Cyberball Task-Related Functional MRI (fMRI): measures of brain activation through...
PMC10652457
MRI Scanning
All scans will be acquired on 3.0 T scanners: Siemens Prisma (Frankfurt, Lausanne), Philips Achieva (CHLA). Signal-to-noise and contrast-to-noise was determined to be comparable across all scanning platforms (Tables Anatomical MRI1.0 mm176 slices1.0 mm176 slicesTask-based fMRI: cyberballResting-State fMRIDiffusion tens...
PMC10652457
Theoretical basis for the fMRI task used in MODE
depressed, trauma
Chronically depressed patients need to experience an intensive, professional, reliable, holding, and containing therapeutic relationship in order to both regain confidence in a "helping object" in the form of the therapist and develop a basic feeling of self-agency. According to psychoanalytic theory, severe early life...
PMC10652457
Task-based fMRI ‘Cyberball’ paradigm
MODE will study the neurobiological mechanisms that subserve this evolving sense of interpersonal trust within patients over the first year of psychoanalytic therapy. We have adapted a task that participants perform while in the MRI scanner so as to identify the brain systems that support the cognitive, emotional, and ...
PMC10652457
Secondary outcome measures
psychiatric, chronic depression, trauma
DISORDERS
MODE will investigate whether and how brain changes are associated with common measures of change for patients with chronic depression and early trauma after one year of treatment. To achieve this aim and as recommended in meta-analytic reviews, various broad areas of patient’s functioning are assessed including (1) ps...
PMC10652457
Assessment of psychopathology
PMC10652457
Diagnosis
SCID
The Structured Clinical Interview for DSM (SCID, [
PMC10652457
Depression
Depressive
Depressive symptoms will be assessed using three instruments: (1) The Inventory of Depressive Symptom (QIDS; [
PMC10652457
Distress
The Symptom Check-List (SCL-90-R; [
PMC10652457
Early life trauma
depressed, trauma
Early childhood trauma is recognized as one of the best predictors of response to psychotherapy for severely depressed patients ( [
PMC10652457
Patient trauma narratives
trauma
Patients will be asked to send a written trauma narrative to the study center with 5 keywords. After the year of study, the research team will send again the keywords to the participant and will ask them to write again their memories on trauma. The trauma narrative will be written freely, with the instruction to write ...
PMC10652457
Dynamic personality functioning
PMC10652457
Psychodynamic functioning and change
psychosomatic disorders, illness
The Operationalized Psychodynamic Diagnosis (OPD) is a form of multiaxial diagnostic system based on five axes: I = experience of illness and prerequisites for treatment, II = interpersonal relations, III = conflict, IV = structure and V = mental and psychosomatic disorders ( [
PMC10652457
Dream diary
chronic depression, trauma
Dreams will be collected in dream diaries ideally at each follow-up points and latest at study termination with the intent to examine dream characteristics in participants with chronic depression and early trauma. Participants can write freely about their dreams. To help participants document their dreams, an exemplary...
PMC10652457
Psychosocial functioning
PMC10652457
Interpersonal problems
The Inventory of Interpersonal Problems (IIP; [
PMC10652457
Interpersonal trust
Primal trust in a helping Other has been proposed as an important feature of therapeutic interaction [
PMC10652457
Therapeutic Alliance
Alliance plays an important role in effective psychotherapy [
PMC10652457
The Global Assessment of Functioning (GAF)
Is a numeric scale (0 through 100) used by an independent coder to rate the social, occupational and psychological level of functioning [
PMC10652457
Work Ability Index (WAI-SR)
A previous study found that short- and long-term psychodynamic psychotherapy were differentially effective in improving work ability [
PMC10652457
MRI Scanning MR spectroscopy (1H MRS)
Scans are acquired on 3.0 T scanners, Siemens Prisma in Frankfurt subgroup only. Spectroscopy was performed at the end of the MRI examination. An axial slice was recorded with 2D MRSI using an acquisition weighted circular phase encoding scheme on a 20 × 20 matrix, FOV of 240 × 240 mm
PMC10652457
Procedures
PMC10652457
Data collection sites
RECRUITMENT
Recruitment and treatment sites will be located in one center in the US (Los Angeles) and six centers in Europe (Germany: Frankfurt a.M., Cologne, Leipzig, Giessen, Mainz; and Switzerland: Lausanne). MRI scanning occurs in Los Angeles, Frankfurt a.M., and Lausanne. MRI data are processed in Los Angeles (CHLA). A clinic...
PMC10652457
Patient recruitment
psychiatric, chronic depression, mood disorders
Patients will be recruited in private psychotherapeutic and psychiatric practices, in outpatient clinics for mood disorders in hospitals. Patient flyers describing study aims and procedures will be available to potential participants with a likely diagnosis of chronic depression. Healthy controls will be recruited thro...
PMC10652457
Presentation of the study and informed consent procedures
chronic depression, trauma
The study will be presented to potential participants. Documents explaining the study, with its aims, procedures, benefits and risks for the participants will be provided to the participants. Interested subjects will be given a period to consider whether they would like to participate and the research team will be at t...
PMC10652457
Randomization
The randomization procedure will consist of a computer-generated sequence of random numbers using SPSS (SPSS Statistics, version 28), which will then be used to allocate patients to either of the 2 treatment arms. The randomization sequence will be generated and maintained by an independent study administrator in Frank...
PMC10652457
Blinding
SCID
All the members of the investigating team (SCID /LIFE interviewers, MRI team etc.) will be blinded (they do neither know the treatment arm nor the names of the study therapists).
PMC10652457
Rater training
SCID
SCID interviewers will be masters-level psychologists, previously trained on administration of SCID and supervised be a senior study investigators.
PMC10652457
Manualized psychotherapeutic interventions
In the LAC study, therapists were trained in the specific treatment technique of psychoanalysis using the Tavistock Manual [
PMC10652457
Therapist selection and training
Both interventions will be delivered by board certified psychoanalytic therapists which have trainings and clinical experiences in low frequent and high frequent psychoanalytic therapies. Trained therapists will deliver both treatments, depending on their availability and vacancies at the time of participant enrollment...
PMC10652457
Clinical supervision
Gilles Ambresin
All study therapists will participate in monthly group supervisions or in one of the monthly “Clinical Conferences” (chairs in Germany: Marianne Leuzinger-Bohleber, Tamara Fischmann, in Lausanne: Gilles Ambresin, in SF/LA: Cheryl Goodrich), where therapists present their ongoing psychoanalyses with study patients.
PMC10652457
Recording and transcription
CPPS
A random selection of therapy sessions will be audiotaped. Adherence to the treatment protocol will be assessed by independent members of the research teams using the Comparative Psychotherapy Process Scale (CPPS; [
PMC10652457
Power calculation
chronic depression
Power analyses using MRI measures from prior RCTs of medication therapy for the treatment of chronic depression [
PMC10652457
Data analysis
depressed
Analyses will follow an intent-to-treat strategy comparing patients in the groups to which they were originally randomized.All data will be scored and rescored by separate staff members and checked for accuracy prior to double entry into a REDCap database. Before conducting inferential statistics, we will explore data ...
PMC10652457
Missing data
We will model missing responses/covariates in our longitudinal models. We will consider missing data mechanisms, including missing completely at random, missing at random, or missing not at random, to handle missing data due to a missed assessment time point, study dropout, or unusable MRIs. The full information maximu...
PMC10652457
Discussion
major depression, trauma
The findings of MODE will be relevant for both clinical and basic research in identifying the brain-based mechanisms whereby psychotherapy exerts its therapeutic effects. MODE is, to our knowledge, the first study to investigate the neurobiological changes in response the effects of intensive psychoanalytic psychothera...
PMC10652457