Evaluation of a Stepped Care Approach to Manage Depression in Diabetes (Ecce_homo)

Efficacy of a Stepped Care Approach to Manage Depression in Diabetic Patients and Putative Inflammatory Mechanisms Between Diabetes and Depression

German Federal Ministry of Education and Research, German Diabetes Center, Heinrich-Heine University, Duesseldorf, University of Giessen, Helmholtz Zentrum München, Coordination Center for Clinical Trials (KKS)

The study examines the efficacy of a stepped care approach for depressed diabetes patients (first study objective). 256 patients with diabetes and comorbid subthreshold or clinical depression will be randomly assigned to either a stepped care approach or a treatment-as-usual condition. The stepped care approach consists of three treatment steps comprising diabetes-specific cognitive-behavioral therapy (CBT) (group), depression-specific CBT (single), and psychotherapeutic and/or psychiatric treatment (single). Patients assigned to the stepped care approach will be treated stepwise until a clinically significant reduction of depressive symptoms is attained or all three treatment steps are passed. The primary outcome of the first study objective is a clinically significant reduction of depressive symptoms in the 12-month follow-up. Secondary outcomes are reduction of diabetes-related distress and improvement of well-being, health-related quality of life, diabetes acceptance, diabetes self-care, and glycaemic control. Additionally, cost-benefit analyses will be performed. The second study objective is to analyse associations between diabetes, depression, and the serum levels of inflammatory markers. The third study objective is to analyse the courses of depressive conditions in diabetes with regard to recovery rates and incidence of major depression.

Compared to persons without diabetes, rates of depressive disorders and mood are doubled in diabetes patients. Epidemiologic studies have shown point prevalence rates of 10 - 14% for major depressive disorder and an additional proportion of almost 20% with subthreshold depression (defined as elevated depressive symptoms without meeting criteria for a specified clinical disorder). Depression and subthreshold depression in diabetes are associated with reduced quality of life, increased diabetes-related distress, and elevated health care costs. Furthermore, depression as well as subthreshold depression seem to be major barriers to an effective self-management of the disease and have been associated with reduced glycaemic control and hyperglycaemia. Both conditions seem to be independent prognostic factors for subsequent morbidity and mortality in diabetes. Depressive conditions are commonly treated with psychotherapeutic or pharmacologic antidepressive therapies. Since the majority of diabetes patients is suffering from subthreshold depression, evaluated and suitable specific intervention concepts are rare. Moreover, the large variation of symptom levels of depressive patient groups suggests that different types of treatment with different treatment intensities may be required to match individual demands. The issue of 'optimal' treatment also regards concerns about overtreatment and undertreatment of particular patient groups with depressive conditions. Thus, an successive order of treatment steps of increasing intensity appears useful. Since depression in diabetes often is associated with high diabetes-related problems and distress, diabetes-specific as well as depression-specific interventions may be required. We developed a stepped care approach with three treatment steps comprising diabetes-specific CBT (group), depression-specific CBT (single), and psychotherapeutic and/or psychiatric treatment (single). The study is a randomized efficacy trial in which the efficacy of the stepped care approach is compared to a treatment-as-usual condition (standard diabetes education). 256 patients with diabetes and comorbid subthreshold or clinical depression will be randomly assigned to either the stepped care approach or the treatment-as-usual condition. Patients assigned to the stepped care approach will be treated stepwise until a clinically significant reduction of depressive symptoms is attained or all three treatment steps are passed. The primary outcome is a clinically significant reduction of depressive symptoms in the 12-month follow-up. Secondary outcomes are reduction of diabetes-related distress and improvement of well-being, health-related quality of life, diabetes acceptance, diabetes self-care, and glycaemic control. The decisive measurement of this outcomes are conducted 12 months after the treatment (12 month follow up). Additionally, cost-benefit analyses will be performed. Besides testing the efficacy of the stepped care approach (first objective), there are two additional study objectives: The second study objective is to analyse associations between diabetes, depression, and the serum levels of inflammatory markers (C-reactive protein (CRP), Interleukin (IL)-6, IL-18, IL-1Ra, Adiponectin, Monocyte chemoattractant protein (MCP)-1). Additionally, the impact of depression treatment on the levels of these markers will be examined. The third study objective is to analyse the courses of depressive conditions in diabetes with regard to recovery rates and incidence of major depression in subclinically or clinically depressed diabetes patients treated as usual vs. given an intervention.

Major Depression, Minor Depression, Sub-Threshold Depression, Affective Condition, Mood Disorder, Light Affective Disorder, Subclinical Depressive Symptoms, Diabetes Mellitus, Diabetes-Related Distress, Self-Care Behaviour, Glycaemic Control, Inflammatory Markers

Step 1: Diabetes-Specific CBT (5 group sessions) Step 2: Depression-Specific CBT (6 single sessions) Step 3: Referral to Psychotherapist and/or Psychiatrist

Diabetes-Specific CBT (5 group sessions) focusing on diabetes-related problems and distress ('DIAMOS - Strengthening Diabetes Motivation'). Includes: Diabetes problem analysis/ definition Diabetes problem solving intervention Cognitive restructuring of diabetes problems Activation of personal and social resources Goal definition and agreement

Depression-Specific CBT (6 single sessions) focusing on depressive cognitions and affective problems (manualised). Includes: Functional explanatory model of depression Cognitive restructuring of negative thoughts Practice of alternative beneficial thoughts Specific cognitive interventions regarding self-criticism, guilt, low self-esteem, fear, and inactivity.

Non-responders to previous treatment steps will be referred to an psychotherapist and/or psychiatrist for intensified treatment. Treatments procedures will be monitored and interventions will be scored to enable the evaluation of treatment effects.

Standard diabetes education and professional care. Includes: Health care and specific topics (e. g. blood pressure) Diabetes complications Healthy and unhealthy foods, cooking recommendations and recipes Foot care: exercises, care and control, injuries, and diabetic neuropathy Sports, activities and exercise Social aspects of living with diabetes

Serum levels of the inflammatory markers CRP, IL-6, IL-18, IL-1Ra, Adiponectin, MCP-1 are assessed to enable analyses with regard to the second study objective - associations between diabetes, depression, and inflammation. The measurement of this additional outcome variable is conducted twice, at baseline and 12 months after the treatment (12 month follow up).

Difference in rates of major depression according to ICD-10 criteria between baseline and 12 months follow up

Inclusion Criteria: Age >=18 and <=70 Diabetes mellitus Elevated depressive symptoms (CES-D score >=16) and/or elevated diabetes-related distress (PAID score >=40) Sufficient language skills (German) Written informed consent Exclusion Criteria: Severe depressive episode (F32.2/ F32.3) Current psychotherapeutic/ psychiatric treatment Current antidepressive medication Suicidal intention Current schizophrenia/ psychotic disorder, specified eating disorder, bipolar disorder, addictive disorder, personality disorder Severe physical illness (i.e. cancer, multiple sclerosis, dementia) Terminal illness Bedriddenness Guardianship

Schmitt A, Kulzer B, Ehrmann D, Haak T, Hermanns N. Diabetes Distress and Depression during COVID-19: Response to Breznoscakova et al. Uncovering the Untold Emotional Toll of Living with Diabetes in the COVID-19 Era. Psychother Psychosom. 2022;91(4):288-289. doi: 10.1159/000524602. Epub 2022 May 6. No abstract available.

Schmitt A, Kulzer B, Reimer A, Herder C, Roden M, Haak T, Hermanns N. Evaluation of a Stepped Care Approach to Manage Depression and Diabetes Distress in Patients with Type 1 Diabetes and Type 2 Diabetes: Results of a Randomized Controlled Trial (ECCE HOMO Study). Psychother Psychosom. 2022;91(2):107-122. doi: 10.1159/000520319. Epub 2021 Dec 7.

Herder C, Schmitt A, Budden F, Reimer A, Kulzer B, Roden M, Haak T, Hermanns N. Association between pro- and anti-inflammatory cytokines and depressive symptoms in patients with diabetes-potential differences by diabetes type and depression scores. Transl Psychiatry. 2018 Mar 9;7(11):1. doi: 10.1038/s41398-017-0009-2.

Herder C, Schmitt A, Budden F, Reimer A, Kulzer B, Roden M, Haak T, Hermanns N. Longitudinal associations between biomarkers of inflammation and changes in depressive symptoms in patients with type 1 and type 2 diabetes. Psychoneuroendocrinology. 2018 May;91:216-225. doi: 10.1016/j.psyneuen.2018.02.032. Epub 2018 Mar 6.

Schmitt A, Reimer A, Kulzer B, Haak T, Gahr A, Hermanns N. Assessment of diabetes acceptance can help identify patients with ineffective diabetes self-care and poor diabetes control. Diabet Med. 2014 Nov;31(11):1446-51. doi: 10.1111/dme.12553. Epub 2014 Aug 2.