Medication-resistant depression (MRD) is associated with poorer attentional performance and immense socioeconomic costs.

We aimed to investigate the central pathophysiology of MRD, previously linked to impaired prefrontal cortex function.

A total of 54 participants (22 with MRD, 16 with non-resistant depression, 16 healthy controls) were recruited. Non-MRD status was confirmed by a prospective 6-week antidepressant trial. All medication-free participants underwent a go/no-go task to study prefrontal cortical function (attention) and positron emission tomography scans to study regional cerebral glucose metabolism (rCMglu) at rest.

The MRD group had worse attentional ratings and decreased rCMglu compared with the non-MRD and control groups. Attentional performance was positively associated with prefrontal cortex rCMglu. The prefrontal cortex differences between MRD and non-MRD groups remained after adjusting for past depressive episodes (F (1,35) = 4.154, P = 0.043).

Pronounced hypofrontality, with the associated attentional deficits, has a key role in the neuropathology of medication-resistant depression.