The trial utilizes a pragmatic, randomized, open label design with two parallel arms. Participants aged 18-65 with a diagnosis of unipolar depressive disorder and without stable remission in the past 12 months are randomized 1:1 to receive either algorithm guided treatment (AGT) or treatment as usual (TAU). The AGT approach incorporates pre-defined treatment steps, critical decision points, and "if-then" rules based on symptom response. It leverages prior treatment history, current symptomatology, and tolerability profiles to personalize the therapeutic sequence and reduce treatment inertia. In contrast, TAU reflects standard clinical practice, where treatment decisions are left to clinician discretion without algorithmic structure. The primary objective of the study is to determine whether AGT leads to a greater reduction in depressive symptoms over a 12-week treatment period, as measured by the 6-item Hamilton Depression Rating Scale (HAMD-6). Secondary objectives include evaluating cognitive and psychosocial functioning, suicide risk, treatment adherence, tolerability, number of medication changes, and long-term outcomes at a 24-week follow-up, providing insights into the longer-term trajectory of TRD management.
A diagnosis of unipolar depressive disorder according to ICD-10 based on documented completion of the Mini International Neuropsychiatric Interview, version 7.0.2 (MINI 7.0.2) at Screening and confirmed by medical records or a healthcare professional.
Have not achieved stable remission of depression in 12 months at investigator's clinical assessment.
Severity of depression: A score of at least 21 on the self-reported Major Depression Inventory (MDI).
Age criteria: Subjects must be at least 18 years old and below 65 at the time of randomization.
A diagnosis of dementia.
Substance misuse influencing study participation as judged by the investigator.
High risk of non-adherence at the investigator's discretion.
Not understanding the Danish language as judged by the investigator.
Parallel
Algorithm guided treatment (AGT)
Other interventionAGTs consist of strategies (which treatments to use), tactics (how to implement each treatment) and treatment steps (in what order to implement the different treatments). Furthermore, AGTs also define critical decision points during the treatment at which the effects of a certain treatment are assessed and based on this assessment recommend specific treatment revisions according to preset "if-then rules." This is most often done by implementing measurement-based care.
Treatment as usual (TAU)
Other interventionTAU includes the standard clinical care for patients with TRD as determined by a senior consultant.
Hamilton Depression Scale, 6 item version (HAMD-6)
The primary outcome measure is the Hamilton Depression Scale, 6 item version (HAMD-6), used as a continuous variable. The primary outcome is the difference in differences (DID) between patients randomized to receive algorithm-guided treatment as compared to treatment as usual, as measured by HAMD-6, based on the mITT population. The 6-item version of the Hamilton Depression Rating Scale ranges from 0 to 22, with higher scores indicating a worse outcome.
HAMD-17
All secondary outcomes are based on the mITT population unless otherwise specified. A Per Protocol (PP) analysis at 12 weeks and at the end of follow-up is performed for all continuous secondary outcomes. Difference-in-difference in HAMD-17. The 17-item version of the Hamilton Depression Rating Scale ranges from 0 to 52, with higher scores indicating a worse outcome.
HAMD-6
Difference-in-difference in HAMD-6 for the PP12 and the PP24 population. The 6-item version of the Hamilton Depression Rating Scale ranges from 0 to 22, with higher scores indicating a worse outcome.
UKU
Difference in difference in UKU adverse events scale
SCIP
Difference-in-difference in Screen for Cognitive Impairment in Psychiatry (SCIP). Values range from 0 to 64+, higher scores indicating a better outcome.
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