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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
80
AGTs 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.
TAU includes the standard clinical care for patients with TRD as determined by a senior consultant.
Aalborg University Hospital
Aalborg, Denmark
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.
Time frame: From baseline to end of study (12 weeks)
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.
Time frame: Up to 24 weeks
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.
Time frame: Up to 24 weeks
UKU
Difference in difference in UKU adverse events scale
Time frame: Up to 24 weeks
SCIP
Difference-in-difference in Screen for Cognitive Impairment in Psychiatry (SCIP). Values range from 0 to 64+, higher scores indicating a better outcome.
Time frame: Up to 12 weeks
FAST
Difference-in-difference in the Functioning Assessment Short Test (FAST). Values range from 0 to 72, higher scores indicating a worse outcome).
Time frame: Up to 12 weeks
COBRA
Difference in difference in Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA). Values range from 0 to 48, higher scores indicating a worse outcome.
Time frame: Up to 12 weeks
CGI
Difference in difference in the Clinical Global Impression Scale (CGI). Values range from 1 to 7, higher scores indicating a worse outcome.
Time frame: Up to 12 weeks
C-SSRS
Difference in difference in the Columbia-Suicide Severity Rating Scale (C-SSRS). Values range from 1 to 5, higher scores indicating a worse outcome.
Time frame: Up to 12 weeks
Between-groups difference in proportion of responders and remitters in HAMD-6 score
Responders are defined as subjects with a reduction of at least 50 % in their HAMD-6 scores between baseline and the endpoint of interest. Remitters are defined as subjects with HAMD-6 score below 5 at the endpoint of interest. Both are measured at 8 weeks or at a premature endpoint before last-observation-carried-forward (LOCF) and at 12 weeks or at a premature endpoint before LOCF.
Time frame: Week 8 and 12
Between-group differences in reason for all cause treatment discontinuation
Between-group differences in reason for all cause treatment discontinuation (lack of effect, lack of tolerability, lost to follow-up, or other cause)
Time frame: Up to 24 weeks
Between-group differences in time to all cause treatment discontinuation
Between-group differences in time to all cause treatment discontinuation
Time frame: Up to 24 weeks
Between-group differences in number of changes in treatment strategies
Between-group differences in number of changes in treatment strategies
Time frame: Up to 12 weeks
Between-group differences in number of changes in the number of different prescribed medications over the treatment period
Between-group differences in number of changes in the number of different prescribed medications over the treatment period
Time frame: Up to 12 weeks
Between-group difference for the ITT population in reasons for premature discontinuation
Between-group difference for the ITT population in reasons for premature discontinuation
Time frame: Up to 24 weeks
Between-group difference for the ITT population in reasons for time to all cause discontinuation
Between-group difference for the ITT population in reasons for time to all cause discontinuation
Time frame: Up to 24 weeks
Between-group difference for the ITT population in adverse events and serious adverse events
Between-group difference for the ITT population in adverse events and serious adverse events
Time frame: Up to 12 weeks
Between-groups difference from original randomization in proportion of responders and remitters at end of follow-up
Between-groups difference from original randomization in proportion of responders and remitters at end of follow-up
Time frame: Up to 24 weeks
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