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.

People with severe depressive illness have raised levels of cortisol and reduced glucocorticoid receptor function.

To obtain a physiological assessment of hypothalamic–pituitary–adrenal (HPA) axis feedback status in an in-patient sample with depression and to relate this to prospectively determined severe treatment resistance.

The prednisolone suppression test was administered to 45 in-patients with depression assessed as resistant to two or more antidepressants and to 46 controls, prior to intensive multimodal in-patient treatment.

The patient group had higher cortisol levels than controls, although the percentage suppression of cortisol output after prednisolone in comparison with placebo did not differ. Nonresponse to in-patient treatment was predicted by a more dysfunctional HPA axis (higher cortisol levels postprednisolone and lower percentage suppression).

In patients with severe depression, HPA axis activity is reset at a higher level, although feedback remains intact. However, prospectively determined severe treatment resistance is associated with an impaired feedback response to combined glucocorticoid and mineralocorticoid receptor activation by prednisolone.