Enhanced post-awakening cortisol may serve as a biological marker for individuals with major depressive disorder. However, studies comparing post-awakening cortisol between patients with major depressive disorder (MDD) and healthy controls have produced conflicting findings. The aim of this study was to investigate whether this inconsistency could be due to the effects of childhood trauma.

A total of N = 112 patients with MDD and healthy controls were divided into four groups according to the presence of childhood trauma. Saliva samples were collected at awakening and 15, 30, 45, and 60 min later. The total cortisol output and the cortisol awakening response (CAR) were calculated.

The total post-awakening cortisol output was significantly higher in patients with MDD as compared to healthy controls, but only in those individuals reporting childhood trauma. The four groups did not differ regarding the CAR.

Elevated post-awakening cortisol in MDD may be confined to those with a history of early life stress. Tailoring and/or augmenting of currently available treatments may be required to meet the specific needs of this population.

Systematic studies on the outcome of treatment-resistant depression are scarce.

To describe the longer-term outcome and predictors of outcome in treatment-resistant depression.

Out of 150 patients approached, 118 participants with confirmed treatment-resistant depression (unipolar, n= 7; bipolar, n=27; secondary, n=14) treated in a specialist in-patient centre were followed-up for between 8 and 84 months (mean=39, s.d.=22).

The majority of participants attained full remission (60.2%), most of whom (48.3% of total sample) showed sustained recovery (full remission for at least 6 months). A substantial minority had persistent subsyndromal depression (19.5%) or persistent depressive episode (20.3%). Diagnosis of bipolar treatment-resistant depression and poorer social support were associated with early relapse, whereas strong social support, higher educational status and milder level of treatment resistance measured with the Maudsley Staging Method were associated with achieving quicker remission. Exploratory analysis of treatment found positive associations between treatment with a monoamine oxidase inhibitor (MAOl) in unipolar treatment-resistant depression and attaining remission at discharge and at final follow-up, and duloxetine use predicted attainment of remission at final follow-up.

Although many patients with treatment-resistant depression experience persistent symptomatology even after intensive, specialist treatment, most can achieve remission. The choice of treatment and presence of good social support may affect remission rates, whereas those with low social support and a bipolar diathesis should be considered at higher risk of early relapse. We suggest that future work to improve the long-term outcome in this disabling form of depression might focus on social interventions to improve support, and the role of neglected pharmacological interventions such as MAOIs.