The Antidepressant Advisor: A Decision Support System for UK Primary Care - a Feasibility Study: Study 3

This prospective observational study focuses on identifying the neural signatures prospectively predicting poor prognosis in MDD patients after receiving four months of treatment in UK primary care.

It is expected that half of the patients will show a response to primary care treatment over the 16 weeks of the trial. This allows for comparison of baseline MRI scans of treatment responders with non-responders. The aim is to recruit at least n=12 in each group with complete data (responders vs non-responders), but if the groups are skewed, a continuous measure (i.e. the difference between final and baseline depression scores) will be used rather than to categorise into responders and non-responders. This sample size is considered sufficient for fMRI studies to run random-effect models. As there is no previous study from which effect sizes can be drawn, the study remains exploratory.

As this study aims to find candidate biomarkers predicting response to antidepressant treatment, it is important to define "response" and "antidepressant treatment". Response to treatment will be defined as a reduction of depressive symptom levels of at least 50%, as assessed by the self-rated Quick Inventory of Depressive Symptomatology (Self-report; 16-Item) from baseline to follow-up.

Due to the range of different antidepressants used in the main trial (Study 1), the primary analysis is to compare responders versus non-responders irrespective of treatment received which ensures the results are of pragmatic relevance to primary care treatment (considered as a complex multifaceted intervention for this study). The following antidepressants are likely to be prescribed in the study, either recommended by the algorithm or as initiated by general practitioners (GPs) without computerised decision support tool advice: sertraline (≥50mg; SSRI), escitalopram (≥10mg; SSRI), mirtazapine (≥30mg; alpha 2 antagonist; NaSSA; dual serotonin and norepinephrine agent), vortioxetine (≥10mg; multimodal), citalopram (≥20mg; SSRI), fluoxetine (≥20mg; SSRI), paroxetine (≥20mg; SSRI), venlafaxine (≥75mg; SSRI up to 150 mg and SNRI>150 mg), duloxetine (60mg; SNRI), therapeutic doses of tricyclics, and therapeutic doses of monoamine oxidase inhibitors.

Further analysis will be aimed at comparing response to another SSRI versus no response to another SSRI. Here, treatment with an SSRI will be defined as treatment with any of the earlier listed SSRIs, as well as low dose venlafaxine (up to 150mg). This includes individuals who started and subsequently stopped their SSRI or did not go up to an effective dose because of presumable side effects (intention-to-treat analysis). However, it excludes individuals whose SSRI has not been changed or whose SSRI dose has not been increased for the study period; individuals whose SSRI remained the same, but the dose increased are included. Individuals who were incompliant with their prescribed SSRI medication are included as their incompliance might be related to experiencing a poor benefit/side effect ratio (intention-to-treat analysis). Individuals who had medications with additional non-SSRI properties are excluded from this analysis (venlafaxine > 150 mg, mirtazapine > 15 mg, antipsychotics, lithium, tricyclics in therapeutic dose, monoamine oxidase inhibitors in therapeutic dose, or vortioxetine).