RESET-psychotherapy: the Effectiveness of Trauma-focused Therapy in Patients With Depression and Childhood Trauma

Depression is a debilitating psychiatric disorder with a recurrent and progressive course. Even though antidepressants and psychotherapy are often effective, a substantial proportion of patients does not respond to currently used evidence-based treatments. Around 25% of depressive patients has experienced moderate to severe levels of childhood trauma (CT), ranging from physical and emotional neglect to emotional, physical and sexual abuse. There is increasing evidence that depression related to childhood trauma (CT) is critically different from non-CT related depression: it emerges earlier in life with more severe and recurrent symptoms and has worse treatment outcomes. Therefore, there is a large and unmet need for novel therapeutic strategies for CT-related depression. Currently, there is no targeted treatment available for CT-related depression. Given the major role of trauma in CT-related depression, it is plausible that trauma-focused psychotherapies may be effective in this depression subtype. The current study aims to investigate the effectiveness of trauma-focused therapy (TFT), as an addition to 'treatment as usual' (TAU), in reducing depression symptom severity in patients with CT-related depression. It is expected that trauma-focused therapy will be a safe and rational strategy to enhance resilience and improve depression outcomes for patients with CT-related depression. RESET-psychotherapy is a 12-week randomized controlled clinical trial (single-blind RCT), in which TFT in combination with TAU will be compared to TAU only at various specialized mental healthcare units of mental health care institutions. The study population will consist of 158 adult patients who have a diagnosis of moderate to severe depression (according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)) and moderate to severe childhood trauma (CT). The primary outcome measure is defined as depression symptom severity after 12 weeks treatment (post-treatment), measured with the Inventory of Depressive Symptomatology - Self Rated (IDS-SR). Data will be collected during multiple assessments: at baseline (T0), after 6 weeks (T1), after 12 weeks (T2; post-treatment), and after 6 months post-treatment (follow-up, T3). Information about depressive symptoms, childhood trauma and other health-related outcomes will be assessed using self-report questionnaires and semi-structured clinical interviews. In addition, to better understand how and for who TFT works, stress-related biomarkers (hair cortisol, inflammatory and epigenetic biomarkers in the blood) will be examined pre- and post-treatment. A sub-group of patients (N=60, 30 per intervention group) will be asked to undergo fMRI scans pre- and post-treatment to measure stress-related brain activity (fMRI sub-study, ±60 minutes per fMRI session).

• Treatment as usual (TAU) for depression (Behavioral): TAU for depression will be largely determined by the Dutch multidisciplinary practice guideline on depression (Spijker et al., 2013). This means that patients with CT-related depression will receive good clinical care, e.g. evidence-based psychotherapeutic interventions, such as cognitive behavioral therapy (CBT) or interpersonal therapy (IPT) combined with/or pharmacotherapy. Therapists who give TAU are not allowed to provide a trauma-focused intervention aimed at CT during the 12-week intervention period.
• Trauma-focused therapy (TFT) (Behavioral): The content of TFT, delivered by another therapist than the therapist that will provide TAU, depends on the type of CT the patient reports. If the patient predominantly reports experiences of abuse, there are often clear memories of this abuse ('target images') present and Eye Movement Desensitization and Reprocessing (EMDR) is recommended as the treatment strategy. If the patient predominantly reports experiences of neglect, memories are often less identifiable, although these experiences can have a big impact on the development of maladaptive schemas. In this case, imagery rescripting (ImRs) is recommended as treatment strategy. If the patient reports both experiences of abuse and neglect, the therapist will discuss with the patient which type of CT has the greatest impact on the current depressive symptoms and starts with the indicated therapy. If indicated, the therapist can switch between EMDR and ImRs after a minimum of 4 sessions.

Primary outcomes

• Depressive symptom severity at post-treatment [Up to 12 weeks (post-treatment)]: Depressive symptom severity in patients with CT-related depression, measured with the Inventory of Depressive Symptomatology - Self Report (IDS-SR, with a total score ranging from 0 to 84, where higher scores indicate higher severity of depressive symptoms)

Secondary outcomes

• Depressive symptom severity during treatment and at 9 months follow-up [Up to 9 months (follow-up)]: Depressive symptom severity in patients with CT-related depression, measured with the Inventory of Depressive Symptomatology - Self Report (IDS-SR, with a total score ranging from 0 to 84, where higher scores indicate higher severity of depressive symptoms)
• Remission in CT-related depression [Up to 9 monts (follow-up)]: The presence or absence of DSM-5 Major Depressive Disorder (MDD), identified using the Major Depressive Disorder (MDD) section of the Dutch translation of the Mini International Neuropsychiatric Interview-Simplified (MINI-S).

Other outcomes

• Functional disability [Up to 9 months (follow-up)]: General functioning and disability in major life domains, measured with the 12-item WHO Disability Schedule (WHODAS; with a total score ranging from 12 to 60, where higher scores indicate more disability or loss of function).
• Anxiety symptoms [Up to 9 months (follow-up)]: The presence and severity of anxiety symptoms, determined with the Beck Anxiety Inventory (BAI; with a total score ranging from 0 to 63, where higher scores indicate higher severity of anxiety symptoms)
• Insomnia [Up to 9 months (follow-up)]: Insomnia severity, measured with with the Insomnia Severity Index (ISI; with a total score ranging from 0-28, where higher scores indicate higher insomnia severity).
• Subjective stress [Up to 9 months (follow-up)]: Subjective stress, determined with the Perceived Stress Scale (PSS; with a total score ranging from 0-40, where higher scores reflect greater perceived stress)
• Suicidality [Up to 9 months (follow-up; if participants report suicidal ideation when completing the IDS-SR or undergoing the M.I.N.I. interview)]: The presence of suicidal ideation or behavior, determined with a shortened version of the Columbia-Suicide Severity Rating Scale (C-SSRS). The suicidal ideation scale ranges from 0-5, where a score of 4 reflects an active suicidal ideation with some intent to act, but without a specific plan and a score of 5 reflects an active suicidal ideation with a specific plan and intent.
• Hair cortisol (stress-related biomarker) [Up to 12 weeks (post-treatment)]: Long-term cortisol levels, assessed by hair samples collected pre - and post-treatment
• Inflammatory markers (stress-related biomarkers) [Up to 12 weeks (post-treatment)]: Levels of C-reactive protein (CRP), Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-6 (IL-6), assessed by blood samples drawn pre - and post-treatment
• Epigenetic markers (stress-related biomarkers) [Up to 12 weeks (post-treatment)]: The DNA, extracted from blood samples drawn pre - and post-treatment, will be used for future exploratory epigenetic research. Epigenetic changes will be analyzed genome-wide using microarrays.
• Brain structure - T1 (fMRI sub-study, not yet started, anticipated start April 2022) [Up to 12 weeks (post-treatment)]: A T1-weighted structural image will be acquired in order to obtain a high-resolution anatomic image of the brain with contrast between grey matter, white matter and CSF (cerebral spinal fluid).
• Brain structure - DTI (fMRI sub-study, not yet started, anticipated start April 2022) [Up to 12 weeks (post-treatment)]: White matter (WM) tract integrity will be investigated by acquiring diffusion tensor images.
• Functional dynamics of spontaneous neural activity (fMRI sub-study, not yet started, anticipated start April 2022) [Up to 12 weeks (post-treatment)]: Resting state fMRI (T2*-weighted echo planar images (EPIs), sensitive to blood oxygenation level-dependent (BOLD) contrast, will be obtained, covering the entire brain under rest)
• Working memory (fMRI sub-study, not yet started, anticipated start April 2022) [Up to 12 weeks (post-treatment)]: Task-based fMRI** (T2*-weighted echo planar images (EPIs), sensitive to blood oxygenation level-dependent (BOLD) contrast, will be obtained, covering the entire brain under rest) ** Precise task to be determined; probably the n-back task or the digit-span task.
• Emotion regulation (fMRI sub-study, not yet started, anticipated start April 2022) [Up to 12 weeks (post-treatment)]: Task-based fMRI (situation-focused volitional reappraisal task; T2*-weighted echo planar images (EPIs), sensitive to blood oxygenation level-dependent (BOLD) contrast, will be obtained, covering the entire brain)
• Reward Processing (fMRI sub-study, not yet started, anticipated start April 2022) [Up to 12 weeks (post-treatment)]: Task-based fMRI (social incentive delay task; T2*-weighted echo planar images (EPIs), sensitive to blood oxygenation level-dependent (BOLD) contrast, will be obtained, covering the entire brain)

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Moderate to severe depression, defined by a score ≥ 26 on the Inventory of Depressive Symptomatology - Self Rated (IDS-SR)
* DSM-5 diagnosis of MDD confirmed with the Dutch translation of the MINI-S for DSM-5
* Moderate to severe childhood trauma (CT) before the age of 18, defined by a score above validated cut-off on one or more of the following domains of the 28-item Childhood Trauma Questionnaire Short Form (CTQ-SF):

  * physical neglect: score ≥ 10
  * emotional neglect: score ≥ 15
  * sexual abuse: score ≥ 8
  * physical abuse: score ≥10
  * emotional abuse: score ≥ 13
* Sufficient mastery of Dutch language

Exclusion Criteria:

* Previous TFT on CT
* Other lifetime severe psychiatric comorbidity (bipolar disorder, psychotic disorder)
* Current alcohol/drug dependence
* Primary diagnosis of post-traumatic stress disorder (PTSD) or Acute Stress Disorder (ASD)
* Lifetime diagnosis of borderline personality disorder (BPD)

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• Christiaan H Vinkers, Prof. dr., Principal investigator, Amsterdam UMC, location VUmc and GGZ inGeest