Rewiring Expectations and Amplifying Rewards: A Study Protocol for a Randomized Controlled Trial of Mechanism-Based Group Psychotherapy for Major Depressive Disorder

Major depressive disorder (MDD) remains a leading cause of disability and often shows incomplete response or relapse after established treatments. A promising strategy is to move beyond broad, symptom-focused interventions toward therapies that directly target the psychological and neurobiological mechanisms maintaining depression. This trial evaluates two mechanism-based, group-delivered psychotherapies that each target a core process implicated in MDD: maladaptive expectation processing and reduced reward sensitivity.

Rationale and mechanistic framework. Expectation pathway. Predictive coding accounts propose that the brain continuously updates prior beliefs in light of new information. In depression, negative expectations about the self, others, and the future often become rigid and resistant to change. Cognitive immunization-discounting or reframing disconfirming evidence-prevents adaptive belief updating, maintains symptoms, and can weaken responses to conventional cognitive-behavioral interventions. Targeting dysfunctional expectations directly-via structured behavioral experiments that produce positive expectation violations and procedures that reduce cognitive immunization-may restore flexibility in belief revision and enhance treatment effects.

Reward pathway. Depressed patients frequently show reduced reward sensitivity, including blunted anticipation of reward and impaired reinforcement learning, processes linked to mesolimbic dopaminergic circuitry (e.g., ventral striatum/nucleus accumbens). These deficits can limit the benefit of nonspecific activity scheduling, which increases exposure to potentially rewarding situations but does not specifically remediate anticipatory and learning-related components of reward processing. Interventions that systematically enhance reward sensitivity and strengthen reinforcement contingencies may therefore improve motivational drive and positive affect.

Neurobiological component. Expectation updating has been associated with activity in the dorsolateral prefrontal cortex (DLPFC) and anterior insula, whereas reward processing consistently engages the ventral striatum and insular cortex. This trial includes a functional MRI (fMRI) module to probe these mechanisms pre- and post-intervention. Participants perform established paradigms tapping threat/expectation learning, future-directed thinking, and social reward/expectation. Linking neural responses to clinical change will clarify how mechanism-based therapies exert their effects and may inform biomarkers for treatment selection and monitoring.

Study design overview. This is a randomized, controlled, superiority trial with three parallel groups: (1) EFPI, (2) REACT, and (3) waiting-list control. The trial follows a 3 × 5 repeated-measures design with planned assessments at baseline (pre-treatment), post-treatment (after 5 weeks), and 3- and 6-month follow-ups. Intervention groups complete all follow-ups; after the 6-month assessment they may initiate further treatment if desired. Waiting-list participants complete baseline and the 3-month follow-up before being ethically permitted to access other treatments. They continue to receive follow-up questionnaires at later time points, including items on additional treatments, to enable sensitivity analyses.