Schema-ECT

Rationale: Electroconvulsive therapy (ECT) is often considered a last treatment option for otherwise treatment resistant depression. Unfortunately, approximately 50% of patients do not respond sufficiently (Heijnen et al., 2010). Furthermore, of the patients who respond initially, 40-80% relapse within half a year (Sackeim et al., 2001). We hypothesize that suboptimal efficacy of ECT could be due to insufficient modulation of negative cognitive schemas, which are relative stable representations of prior knowledge and experiences. These negative schemas distort the perception of new experiences in a maladaptive manner, and focus one’s thoughts on negative aspects of oneself. Cognitive theories of depression hold that these negative schemas play an important role in the development, maintenance and recurrence of depression (Beck and Clark, 1988). We recently found that memories can be weakened by applying ECT shortly after reactivation of a memory (Kroes et al., 2013). This suggests that reactivation of negative schemas just prior to ECT may also weaken those schemas. According to the cognitive theory of depression this will lead to the recovery from depression and will additionally reduce the risk to relapse, but this has not yet been investigated. Here, we aim to investigate the efficacy of “schema-ECT” and hypothesize that repeated reactivation of depressive schemas prior to ECT weakens negative schemas, increases the efficacy of the ECT course, and reduces the relapse rate after the reduction of the ECT session frequency or discontinuing ECT. In addition to our main aim, we will investigate whether the clinical response to ECT response is associated with changes in neurobiological biomarkers using neuroimaging scans and blood samples obtained from the venous catheter, and whether these biomarkers at baseline can predict treatment response (van Waarde et al., submitted).

Objective: Our primary objectives are to determine whether schema-ECT increases the remission rate of a course of ECT, reduces the relapse rate, and weakens negative schemas. Our secondary objectives are to identify neurobiological biomarkers that predict and are associated with treatment response.

Study design: A randomized controlled trial (RCT) is used to determine schema-ECT efficacy. Neuroimaging and blood biomarkers will be associated with changes in clinical variables.

Study population: 98 patients with a primary diagnosis of major depressive disorder (MDD) and an indication for ECT between 18-70 years of age. Eligible candidates for MRI will be asked to participate in the neuroimaging experiment.

Intervention (if applicable): Patients will be randomized to schema-ECT or control-ECT, stratified for research center. Schema-ECT consists of reactivation of depressive schemas using the arrow-down technique that is used in cognitive-behavioral therapy (CBT). In the control condition, patients will be interviewed about details that are also of clinical relevance but are not expected to activate depressive schemas (e.g., their medical record, diet, exercise). ECT is performed according to the national guidelines, which consists of a minimum of 6 biweekly sessions until remission or a plateau in response is achieved.

Main study parameters/endpoints: Treatment efficacy as measured with the Hamilton Rating Scale for Depression (HAM-D; 17-items). Response is defined as a 50% reduction and remission as a score 7. The influence on negative schemas is measured with the Dysfunctional Attitude Scale (DAS), the Automatic Thoughts Questionnaire (ATQ), and the Self-Referent Encoding Task (SRET). Neuroimaging biomarkers are hippocampal magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), and resting-state functional magnetic resonance imaging (fMRI). Blood biomarkers will be determined from blood samples obtained from the venous catheter that is placed for anaesthesia induction during the treatment phase or venapuncture at follow-up.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The burden of ineffectively treated depression is high. The burden of ECT is considerable but is warranted because of successful treatment, and its risk can be
considered negligible. Importantly, only the regular ECT-population will be recruited. The additional burden for participating in this study is minimal and the additional risk can be considered negligible. Because the treatment under investigation is expected to increase the efficacy of ECT, patients may directly benefit from participating in this study. The additional burden for participating in the neuroimaging study can be considered minimal, and the additional risk for eligible candidates is negligible. The additional burden for blood sampling from the venous catheter that is already placed as part of the ECT procedure can be considered minimal and the risk negligible.

We recently found that memories can be weakened by applying electroconvulsive therapy (ECT) shortly after reactivation of a memory (Kroes et al., 2014). This suggests that reactivation of negative schemas just prior to ECT may also weaken those schemas. According to the cognitive theory of depression this will lead to the recovery from depression and will additionally reduce the risk to relapse, but this has not yet been investigated. In this study, we aim to investigate the efficacy of “schema-ECT” and hypothesize that repeated reactivation of depressive schemas prior to ECT weakens negative schemas, increases the efficacy of the ECT course, and reduces the relapse rate after the reduction of the ECT session frequency or discontinuing ECT.
In addition to our main aim, we will investigate whether the clinical response to ECT response is associated with changes in neurobiological biomarkers using neuroimaging scans and blood samples obtained from the venous catheter, and whether these biomarkers at baseline can predict treatment response.

Pre-treatment baseline measures are obtained before start of ECT. During treatment, HAM-D scores are obtained at least every 6 sessions to follow treatment response. Within one week after the last ECT session (and before the transition of possible maintenance ECT (<1 session per week)), all parameters are assessed again as post-treatment measurement. Thereafter, patients are evaluated at 2-week intervals the first 8 weeks, and at 4-week intervals for the remaining 12 weeks to determine possible treatment relapse.

The subjects will be randomised to schema-ECT or control-ECT. ECT is conducted as usual according to national guidelines in both patient groups (Nederlandse Vereniging voor Psychiatrie, 2010). In the schema group, ECT is preceded by a structured interview using the arrow-down technique, a technique known from cognitive-behavioral therapy (CBT) to reactivate negative schemas. In the control condition, patients will be interviewed about details that are also of clinical relevance but are not expected to activate depressive schemas.