The aim of this clinical trial is to investigate the effects of a three-week virtual reality-based cognitive remediation training (VR-CRT) programme in combination with daily intake of a histone deacetylase inhibitor (HDACi) sodium butyrate on cognition in symptomatically stable patients with mood disorders (depression or bipolar disorder).

The investigators hypothesize that the VR-based cognitive remediation training (VR-CRT) combined with HDACi butyrate vs. a VR-based control treatment combined with placebo will improve global cognition (primary outcome measure) over three weeks.

Secondly, the investigators hypothesize that VR-CRT with placebo will improve cognition relative to the VR control treatment with placebo, although to a lesser extent than VR-CRT with HDACi butyrate.

Thirdly, the investigators hypothesize that the HDACi butyrate with VR control treatment will not produce cognitive improvements relative to placebo with VR control treatment.

Finally, the investigators hypothesize that the combined treatment (VR-CRT + HDACi butyrate) will enhance neuroplasticity (exploratory outcome) vs. VR control with placebo, as indicated by increase in hippocampal volume and/or memory-related activity shown with structural and functional MRI.

The present study will include middle-age to older (40-75) outpatients with mood disorders (major depressive disorder or bipolar disorder) in full or partial remission (symptomatically stable) at the time of inclusion (≤ 14 on the Hamilton Depression Rating Scale - HDRS-17 or the Young Mania Rating Scale - YMRS). To accommodate an approximated drop-out rate of 15% from baseline to treatment completion (primary outcome assessment time point), the investigators will recruit up to 160 participants until full data sets are obtained for 120 participants (30 participants per arm).

Recruitment will be carried out through the outpatient Copenhagen Affective Disorder Clinic, other mental health centers in the Capital Region of Denmark, through consultant psychiatrists in the Capital Region and through advertisements on relevant websites.

After inclusion, baseline assessments are scheduled and completed over two days, one to five days apart. Participants are assessed with a VR-based virtual cognition test (CAVIR), and a comprehensive neuropsychological cognitive test battery. Participants also complete questionnaires concerning subjective cognitive complaints, quality of life, and personality traits. Psychosocial functioning is assessed using a clinician-rated interview and a performance-based assessment. Finally, sleep quantity and quality in the past 3 days is recorded. Within +/- 3 days an fMRI scan is carried out encompassing a spatial working memory N-back task, a word encoding paradigm in which participants encode and recall words of typical household items, an affective picture encoding test, in which participants denote the orientation (left/right) of emotionally valent pictures (incidental encoding), resting state, and a structural scan. After the scan, participants are asked to recall the emotional pictures encoded during the scan.

The virtual reality cognition test, neuropsychological assessments, questionnaires, clinical symptom ratings, assessment of psychosocial functioning and fMRI scan are repeated within 2 weeks of treatment completion (primary outcome assessment time). All assessments but fMRI are repeated again 1 month (4 weeks) after treatment completion.

Block randomization is carried out using the automated randomization module in the online Research Electronic Data Capture (REDcap) system based on an uploaded blocked randomization list stratified by age (< or ≥ 60 years) and diagnosis (major depressive disorder or bipolar disorder).

Inclusion Criteria:

• Confirmed ICD-10 diagnosis of BD or recurrent UD in partial, or full remission (Hamilton Depression Rating Scale-17 items and Young Mania Rating Scale scores ≤14)
• Subjective cognitive complaints (self-reported: COBRA ≥12) or objectively-verified cognitive impairment (measured using Screening for Cognitive Impairment in Psychiatry SCIP: total score or at least two subscores ≥ 0.5 SD below expected norms)
• Fluency in Danish language

Exclusion Criteria:

• Diagnosis of schizophrenia
• Neurological disorders (including dementia)
• Dyslexia
• Severe Physical illness
• Kidney disease
• Cardiovascular disease
• Diabetes
• Alcohol or substance abuse
• Previous severe head trauma
• History of epilepsy
• Pregnancy or breastfeeding
• BMI >30
• Bodyweight < 45kg
• Daily use of benzodiazepines > 22.5 mg. oxazepam or > 7.5 mg. diazepam per day
• Serum lithium levels > 0.8 mmol/L
• Received electroconvulsive therapy < 2 months prior to participation
• Hypertension (>140 systolic or > 90 diastolic mm Hg)