A Comparison of Two Psychotherapy Programs in Persistently Depressed Treatment-Resistant Inpatients (ChangePDD)

Cognitive Behavioral Analysis System of Psychotherapy (CBASP) vs. Behavioral Activation (BA) in Persistently Depressed Treatment-resistant Inpatients: Efficacy, Moderators, and Mediators of Change

German Research Foundation, University of Kassel, University Medicine Greifswald, Charite University, Berlin, Germany, Hannover Medical School, University Hospital Lübeck, Philipps University Marburg Medical Center, Ludwig-Maximilians - University of Munich, University Hospital Tuebingen

The purpose of this study is to compare the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) conducted over 16 weeks (acute and continuation treatment) with Behavioral Activation (BA; same dose and duration) in persistently depressed treatment-resistant inpatients regarding efficacy, moderators and mediators of change.

About half of all psychiatric inpatients with depression suffer from persistent depressive disorder (PDD). Given their high degree of treatment-resistance (TR), comorbidity, suicidality, and hospitalization rates, this patient group appears to be particularly difficult to treat and, from a health economic perspective, constitutes a major challenge. The Cognitive Behavioral Analysis System of Psychotherapy (CBASP) is the only psychotherapy specifically tailored for PDD developed. Originally developed as an outpatient treatment by James P. McCullough, CBASP has been modified for the severely ill PDD patients with TR as a multimodal inpatient concept. Pilot studies indicate very good feasibility and promising outcome. Therefore, a randomized controlled trial is now mandatory for testing the superiority of the inpatient CBASP program vs. the evidence-based Cognitive Behavioral Therapy (CBT), the 'gold standard' in depression treatment. Behavioral Activation (BA) was chosen as the control intervention because BA, as a specific variant of CBT, is at least as effective as standard CBT in severely depressed patients while being easier to train and implement in inpatient settings. Both therapies will be applied as a treatment-phase program (5-week inpatient and dayclinic acute treatment followed by 6-week outpatient continuation group-treatment) in combination with standardized and guideline-based pharmacotherapy. The proposed prospective, multi-center, randomized study with 396 PDD patients with TR will therefore address the primary research question: Is the CBASP program more effective than the BA program in this patient group? The primary hypothesis is that after 16 weeks of treatment, CBASP will show a significant superiority over BA in reducing depressive symptoms. In addition, the important psychotherapy research question: what works for whom and why? will be addressed. Moderator analyses will examine whether childhood maltreatment and methylation of exon IV of the BDNF gene have an impact on the differential efficacy of the treatments. Regarding mediator analyses, it will be examined whether symptom improvements can be explained by an amelioration of interpersonal problems in CBASP and an increase of activity levels in BA. A follow-up survey 48 weeks after the end of the interventions will provide valuable results regarding the long-term outcome of the treatments. Finally, the health economic potential of the interventions will be investigated through cost-benefit analyses in order to provide important information on the cost-effectiveness of implementation in routine care for health policy. Thus, the results of this study will have the potential to relieve the burden of this very serious and cost-intensive disorder while improving human health. In addition, moderator and mediator analyses may guide personalized treatment and enable therapists to more specifically address psychotherapeutic needs of individual PDD patients in the future.

Psychotherapy, Depression, Inpatient Treatment, Childhood Maltreatment, Epigenetic, Moderator, Mediator, Efficacy

Prospective, multicenter, evaluator-blinded, parallel-group, randomized controlled intervention trial with an active control condition

Due to the nature of interventions, blinding of patients/therapists concerning the treatment program is impossible, but all assessments as well as data analysis will be blinded to treatment allocation. Notably, patients are blinded to the study hypothesis by the Informed Consent process, as patients are told in the patient information and educational discussions about the study that they will in any case receive one of two different scientifically based psychotherapy programs, although it is unclear which of the two programs is more effective. Similarly, the members of the treatment teams of each study ward are not informed about the study hypothesis; however, they are informed that it has not yet been scientifically clarified which therapy is more effective.

Cognitive Behavioral Analysis System of Psychotherapy (CBASP) as acute treatment (5 wk. inpatient and 5 wk. either inpatient or dayclinic) followed by continuation treatment (6 wk. outpatient group therapy).

Behavioral Activation (BA) as acute treatment (5 wk. inpatient and 5 wk. either inpatient or dayclinic) followed by continuation treatment (6 wk. outpatient group therapy).

During the 5-week inpatient phase I and the 5-week inpatient phase II / dayclinic treatment all patients in this arm will receive 2 individual CBASP therapy sessions (duration: 50 min per session).

During the 5-week inpatient phase I and the 5-week inpatient phase II / dayclinic treatment all patients in this arm will receive 2 CBASP group therapy sessions (duration: 100 min per session).

During the 5-week inpatient phase I and the 5-week inpatient phase II / dayclinic treatment all patients in this arm will receive 1 CBASP nurse contact (duration: 30 min per session).

During the 5-week inpatient phase I and the 5-week inpatient phase II / dayclinic treatment all patients in this arm will receive 1 CBASP exercise therapy (duration: 75 min per session).

During the 6-week outpatient treatment all patients in this arm will receive 1 CBASP group therapy session (duration: 100 min per session).

During the 5-week inpatient phase I and the 5-week inpatient phase II / dayclinic treatment all patients in this arm will receive 2 individual BA therapy sessions (duration: 50 min per session).

During the 5-week inpatient phase I and the 5-week inpatient phase II / dayclinic treatment all patients in this arm will receive 2 BA group therapy sessions (duration: 100 min per session).

During the 5-week inpatient phase I and the 5-week inpatient phase II / dayclinic treatment all patients in this arm will receive 1 BA nurse contact (duration: 30 min per session)

During the 5-week inpatient phase I and the 5-week inpatient phase II / dayclinic treatment all patients in this arm will receive 1 BA exercise therapy (duration: 75 min per session).

During the 6-week outpatient treatment all patients in this arm will receive 1 BA group therapy session (duration: 100 min per session).

All patients will receive an optimized, algorithm-based antidepressant medication following the current S3-Guidelines on Unipolar Depression. In case of nonresponse: 1st line dose escalation (if appropriate) 2nd line lithium augmentation 3rd line augmentation with 2nd generation antipsychotics or evidence-based combinations of antidepressants 4th line change of antidepressant.

The change in HDRS-24 item score after 16 weeks will be the primary endpoint. The HRSD-24 is a semi-structured interview which is used to measure the severity of all symptom domains of depression as described by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) over a period of the last 7 days. It shows good psychometric properties. The HRSD-24 will be conducted by blind study raters at every time point. Raters evaluate symptom severity on a scale from 0 to 2 or 0 - 3 or 0 - 4 for each item, with higher number indicating higher symptom severity. The total score ranges from 0 to 75 with higher values indicating higher depression severity.

The HDRS-24 is a semi-structured interview which is used to measure the severity of all symptom domains of depression as described by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) over a period of the last 7 days. It shows good psychometric properties. The HDRS-24 will be conducted by blind study raters at every time point. Raters evaluate symptom severity on a scale from 0 to 2 or 0 - 3 or 0 - 4 for each item, with higher number indicating higher symptom severity. The total score ranges from 0 to 75 with higher values indicating higher depression severity.

The IDS-SR is a self-reported measure of depressive symptoms and used to detect change in self-rated depression severity. It shows good psychometric properties. Each item is rated from 0 to 3 by the patient, and all values are added up to an overall score. Total score ranges from 0 to 78, with higher values indicating a higher depression severity.

The BSI is a multi-dimensional self-reported measure with a total of nine scales assessing the subjective impairment by physical and psychological symptoms. Each item is rated on a scale from 0 to 5 by the patient and are added up and t-transformed to three global indices: Global Severity Index, Positive Symptom Distress Index, Positive Symptom Total. T-Scores range from 0 to 100, with higher values indicating a higher subjective impairment.

The GAF is a diagnostic measure used to assess social, occupational and psychological functioning according to DSM-IV. The score ranges from 0 to 100 with a total of ten levels of functioning and is determined by a clinical rater. Higher scores indicate a higher level of functioning and therefore a better outcome.

The WHOQoL-BREF is a self-reporting measure regarding the subjective quality of life. Four broad domains of quality of life are rated by the patient on a five point scale and a mean score for each domain is calculated. Scores range between 4 and 20, with a higher score indicating a higher quality of life and therefore a better outcome.

Relapse rates (rehospitalization, increase of HDRS-24 of equal or greater than 10 or current HDRS-24 score of equal or greater than 18 points) are measured.

The cost interview assesses direct medical and non-medical costs and indirect costs due to mental disorders versus physical illnesses.

Childhood maltreatment by the definition of the World Health Organization (WHO) is assessed as a main moderator at baseline. The CTQ measures self-reported childhood trauma on five subscales. Responses are measured on a five point scale, and each subscale score has a range from 5 to 25 points. Higher scores indicate a higher severity in childhood trauma and therefore a worse outcome.

The IIP-32-R is a self-reported questionnaire that assesses the severity of interpersonal problems on eight scales based on the two-dimensional interpersonal circumplex model as a main mediator. The items are rated on a five-point scale by the patients. A mean score is calculated, ranging from 0 to 4. A higher score indicates a higher severity of interpersonal problems and therefore a worse outcome.

This self-report is designed to measure weekly changes in avoidance and activation during treatment with Behavioral Activation for depression. The BADS consists of 25 questions on four subscales, each rated on a seven point scale ranging from 0 to 6. The subscales are activation, avoidance/rumination, work/school impairment, and social impairment. A higher total score represents a higher level of activation and therefore a better outcome, while a high score in the subscale social impairment indicates a higher level of impairment and therefore a worse outcome. Scores range from 0 to 150.

Inclusion Criteria: Primary DSM-5 diagnosis of PDD (300.4, 296.2x, 296.3x) Total Hamilton Depression Rating Scale (HDRS-24) Score ≥ 20 Treatment-resistance (TR) (defined as a level of 3 or higher on the Antidepressant Treatment History Form: Short Form (ATHF-SF) or medication intolerance or one psychotherapy at least 25 sessions by a certified therapist in the current episode) Sufficient knowledge of the German language Written informed consent Exclusion Criteria: Bipolar I or II disorder Active substance use disorders (abstinence shorter than 6 months) Schizophrenia spectrum and other psychotic disorders Antisocial personality disorder Acute suicidality Previous CBASP or BA treatment within the last year Inability to tolerate CBASP or BA (e.g., organic brain disorders, severe cognitive deficits) Inability to participate in dayclinic or outpatient continuation treatment

In accordance with the Open Science specifications of the German Psychological Association (DGPS), anonymized data will be made available to the public via the Open Data portal of the Open Science Foundation (www.osf.io). The data will be stored when data collection is completed, but not before 01.01.2028. This step allows third parties to reproduce the analyses reported in scientific publications and to perform ad hoc analyses. The data is permanently stored on servers located in Germany. As soon as they are uploaded and published, these anonymized data cannot be deleted and are therefore also excluded from the deletion of the data in case of revocation of the study participation.

We will make the outcome data and then the covariate data freely available after our respective publications, but not before 01.01.2028.

data will be shared with the public; data will be made available for all what types of analyses; the mechanism by which the data will be made available will be determined soon.

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