Up to one-third of patients with depression develop persistent depressive disorder (PDD). This occurs with an estimated lifetime prevalence of between 3% and 6% (Angst et al., 2009; Murphy & Byrne, 2012). Considering the high degree of suicidality, comorbidity, and resistance to outpatient treatment (Murphy & Byrne, 2012; Bschor et al., 2014; Murphy et al., 2017; Köhler et al., 2019), many PDS patients require inpatient treatment according to the guidelines. Approximately half of all patients with inpatient treatment for depression suffer from PDS (Härter et al., 2004; Hölzel et al., 2010; Bschor et al., 2014; DGPPN et al., 2015; Köhler et al., 2016). In Germany, approximately 70,000 PDD patients are currently treated as inpatients each year. This results in enormous economic burdens, estimated at around €1 billion annually. Accordingly, these patients represent one of the main cost factors in the treatment of depression (Luppa et al., 2007). However, there is currently no evidence-based treatment for this patient group (Köhler et al., 2016; Schefft et al., 2019). Although there is evidence of the effectiveness of inpatient psychotherapeutic treatments in the treatment of patients with depression (Keller et al., 2001), PDS patients show a low response rate, report higher dissatisfaction with treatment, and show a higher risk of relapse after discharge than inpatients with acute depression (Härter et al., 2004; Keller et al., 2001). Accordingly, new treatment programs are urgently needed (Köhler et al., 2016; Schefft et al., 2019) to reduce this resistance to therapy. The study presented here aims to compare the effectiveness of two therapy programs, CBASP and BA, which will be described in more detail below, in order to provide the necessary scientific basis for improved, evidence-based treatment of persistent depressive disorder. In addition, the important research question of individualized psychotherapy will be addressed:

The aim of this study is to compare the effectiveness of a newer therapeutic method developed specifically for this condition (called ‘CBASP’) with an already established psychotherapy (called ‘BA’) in patients with persistent depression who have not responded adequately to other therapeutic attempts to date.
This clinical study therefore aims to answer the primary research question of which of the two therapeutic approaches is more effective in the patient group with persistent depression. Moderator analyses will also provide information on whether a history of child abuse and BDNF methylation have an influence on the differential effectiveness of the methods. With regard to mediator analyses, we will investigate whether symptom improvement can be explained by a positive change in interpersonal problems in CBASP and an increase in activity in BA. A follow-up examination 48 weeks after the end of treatment will also provide results regarding the sustainability and long-term effectiveness of both treatments.
Finally, the health economic potential of both interventions will be examined using cost-benefit analyses to provide important health policy information regarding the economic aspects of implementing both approaches in routine care. This clinical study therefore has the potential to reduce the enormous burden of this serious and costly disease and improve mental health. In addition, moderator and mediator analyses can provide important insights for personalized treatment decisions in patients with persistent depression.

This prospective, multicenter, randomized study aims to compare the two manual-based inpatient treatment programs CBASP (Brakemeier & Normann, 2012; Brakemeier, Guhn & Normann, in press) and BA (Martell et al., 2015) in treatment-resistant patients with persistent depressive disorder (PDD).

396 patients who meet the inclusion and exclusion criteria will be randomly assigned to one of the two study arms. Both therapy programs consist of ten weeks of acute treatment and six weeks of maintenance therapy. The acute treatment comprises ten weeks of inpatient care, with the last five weeks optionally also being carried out on an outpatient basis. This is followed by six weeks of outpatient group therapy as maintenance therapy. After a total of 16 weeks of treatment, patients are observed in a naturalistic follow-up for 48 weeks. To ensure standardization and comparability, treatments are carried out according to corresponding treatment manuals at each study center in two trained specialized wards.

Various instruments are used in study visits, which are either completed by patients themselves or conducted as interviews by clinically trained raters. Our primary endpoint is the change in depressive symptoms based on the HAMD-24 (Hamilton, 1960; Williams, 1988). Secondary endpoints include depressive and anxiety symptoms (HAMD-24, IDS-SR), other relevant psychological variables (such as BSI; Derogatis & Spencer, 1993, GAF; Hall, 1995, WHOQoL; Angermeyer et al., 2000), response, remission, dropout, and relapse rates (measured using HAMD-24), and cost-effectiveness (cost interview; Wagner et al., 2014). In addition, an analysis of potential moderators (childhood maltreatment, CTQ; Bernstein et al., 2003; Wingenfeld et al., 2010; BDNF methylation) and mediators (interpersonal problems, IIP-32-R; Horowitz et al., 2000, activity measured using a pedometer) in order to answer the important psychotherapy research question: What works for whom, and why?

Behavioral Activation (BA; Kanter et al., 2009; Martell et al., 2015) is an equally effective (Cuijpers et al., 2007; Dimidjian et al., 2006; Spates et al., 2006; Shinohara et al., 2013; Richards et al., 2016) variant of established Cognitive Behavioral Therapy (CBT), the "gold standard" in the treatment of depression. Its focus is on how individuals interact with their environment. The goal is to increase activity in patients' individual value domains by reducing barriers and developing specific behavioral skills. BA can be used in both outpatient and inpatient settings (Snarski et al., 2011).

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