Table 1 Sub-studies: data collected and rationale

Neuropsychological function

CANTAB spatial working memory (SWM) task [36].

The neuropsychological tasks have chosen on the basis of their known sensitivity to cortisol and/or 5-HT manipulations. For example SWM has been shown to be sensitive to corticosteroid manipulations in healthy controls and patients [37–39]. The FEERT, ECMT and affective go/no-go tasks, on the other hand have strong evidence for sensitivity to 5-HT manipulations [40–42], while episodic verbal memory, as tested with the VTL) is sensitive to both corticosteroid and 5-HT manipulations [43–45]. Changes in performance of the tasks following metyrapone treatment will help identify whether any improvements with the treatment may be associated with changes in HPA axis function and/or 5-HT neurotransmission.

80 patients, equal numbers from each treatment arm. 50 patients recruited in Newcastle and 30 in Manchester.

Patients – week 0 and 5

Verbal Learning Test (VTL) comprising neutral, positive and negative emotional words with immediate and delayed recall and recognition trails.

Healthy Controls – week 0

55 healthy controls.

Object-Location Memory (OLM) paradigm [46].

Digit Span – forward and backward.

Attentional Network Test (ANT) [47].

Facial Emotional Expression Recognition Test (FEERT) [48].

Emotional Categorisation and Memory test (ECMT) [48].

Affective Go/No Go Task [49].

EEG: Treatment response prediction

Alpha power.

This sub-study will utilise a range of EEG variables with an evidence base for predicting response to monoaminergic antidepressants [50]. The LDAEPs have been shown to differentially predict response to serotonergic versus noradrenergic antidepressants [51]. We predict that the relationship between clinical response and LDAEP measurement will be consistent with serotonergic enhancement by metyrapone.

50 patients, equal numbers from each treatment arm, recruited in Newcastle.

Alpha hemispheric asymmetry.

Patients – week 0 and 5

Theta power localised to anterior cingulate.

Healthy Controls – week 0

25 healthy controls.

Loudness dependency of auditory evoked potentials (LDAEPs).

EEG: Neural correlates of emotional processing and memory

Emotional source memory task (ESMT) [52].

The ESMT task will examine the neural correlates of emotional episodic memory in patients and the effects of metyrapone treatment. This will supplement the information provided in the VTL in the neuropsychological sub-study described above.

50 patients, equal numbers from each treatment arm, recruited in Newcastle.

Putative EEG measure of long-term potentiation (LTP) [55].

25 healthy controls.

The putative LTP measure has previously been shown to be impaired in depressed patients [53] and LTP is known to be sensitive to corticosteroids in animals [54]. We predict that treatment with metyrapone will normalise potential impairments in this measure in the patient cohort.

Patients – week 0 and 5

Healthy Controls – week 0

Newcastle fMRI sub-study

Facial emotional processing task (FEPT) [56].

FEPT allows investigation of a functional cortical network involved in the processing of emotions and emotional responses. It supplements information obtained using the FEERT in the neuropsychological sub-study described above and enable localisation of any effects seen. Likewise the EEMET will supplement the information provided in the VTL.

30 patients from NE Hub - equal number from each treatment arm.

Patients – week 0 and 5

Emotional episodic memory encoding task (EEMET) [57].

Healthy Controls – week 0

15 healthy controls matched for age, handedness and IQ.

Manchester fMRI sub-study

Neural correlates of episodic and working memory.

The episodic memory task will involve encoding and recall of neutral and emotionally valenced pictures, while the working memory task will utilise the N-back task. This will further supplement the data obtained in the neuropsychological sub-study.

30 patients from NW Hub - equal number from each treatment arm.

Patients – week 0 and 5

Hydrocortisone pharmacoMRI [58].

30 healthy matched controls.

For the pharmacoMRI, at week 0 patients receiving metyrapone will receive a 100 mg hydrocortisone bolus and those receiving placebo saline. Healthy controls will be randomised to hydrocortisone or saline. At week 5 all patients will receive hydrocortisone. We predict that blunted acute hippocampal responses to hydrocortisone pre-treatment will normalise after metyrapone, but not placebo, treatment.

Healthy Controls – week 0

Genotyping

We will look for an association between treatment outcome, its predictors and genetic polymorphisms and also for genetic influences on brain information processing (for example brain derived neurotropic factor (BDNF) and corticotrophin releasing factor (CRF) variants and hippocampal response to hydrocortisone in Manchester/amygdala response to emotional faces in Newcastle). We will also investigate the DNA samples for rare genetic variants (e.g. copy number variations). We will determine our candidate gene list based on previous candidate gene association studies and recent novel findings from genome-wide association studies with major depressive disorder and by considering relevant genes for the function of the HPA axis.

All patients and healthy controls approached for specific consent to provide a DNA sample.

Patients and Controls