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.

The study period consists of 12 weeks in the randomized phase and 12-week extended follow up period during which all participants are monitored and treated at the clinician's discretion. After baseline, study visits are planned at 4, 8, 12 and 24 weeks.

Inclusion Criteria:

1. 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.
2. Have not achieved stable remission of depression in 12 months at investigator's clinical assessment.
3. Severity of depression: A score of at least 21 on the self-reported Major Depression Inventory (MDI).
4. Age criteria: Subjects must be at least 18 years old and below 65 at the time of randomization.
5. Signed document of informed consent.
6. The participant is an outpatient.
7. No significant change in medical treatment in the last 4 weeks before screening visit.
8. The patient is pharmacologically treated for depression.

Exclusion Criteria:

1. A diagnosis of dementia.
2. Substance misuse influencing study participation as judged by the investigator.
3. High risk of non-adherence at the investigator's discretion.
4. Not understanding the Danish language as judged by the investigator.
5. Suicidality according to C-SSRS with a positive response to question 4 or 5 within the last three months or upon investigator's discretion.
6. Medical conditions such as cancer, kidney failure, epilepsy, deep brain stimulation device, or other medical conditions interfering with study the outcome and safety as judged by investigator's discretion.