The efficacy of transcranial direct current stimulation (tDCS) in the treatment of depression and brain functional changes compared to venlafaxine

INTERVENTION: Part one: Single‐centre double‐blind randomised parallel trial Following an initial wash‐out period (5‐7 days), eligible subjects will receive 4‐week treatment. They will be randomly allocated according to permuted block design with a fixed block size 4, in a 1:1 ratio (no stratification) to either tDCS + placebo group or venlafaxine + placebo stimulation group. Both groups will also receive hydroxyzine (maximum 100 mg/day) for anxiety and zolpidem for insomnia during the study. The continuation of benzodiazepine medication will be allowed in unchanged dosage in patients who used them before the study. Participants who do not respond to treatment in the acute phase of study will be treated as usual according to their psychiatrists. Group 1: Venlafaxine extended release (ER) + placebo stimulation Patients assigned to venlafaxine treatment will take 75mg of venlafaxine ER for the first 5 days of the study period. From day 6 onward, the dose could be increased every 5 days by 75 mg to maximal dose (375mg/day) according to the clinical judgment of the attending physician. Patients who will not tolerate at least 150mg of venlafaxine ER/day will be excluded from the study. The placebo stimulation will be delivered in the same anatomical location with identical stimulation parameters as real stimulation but the device will be turned‐off after 1 minute of active stimulation. Group 2: Transcranial direct current stimulation (tDCS) + placebo medication The tDCS montage will comprise placement of the anode over the F3 area and cathode over the F4 area (corresponding to the left and right DLPFC according to 10‐20 EEG system). Rubber electrodes will be inserted in 25‐cm2 saline and gel soaked sponge and fixed with a headband to stimulation area. Each week day (altogether 20 sessions), subjects will receive a direct current of 2mA (current density 0.08 mA/m2 for 30 min/ day). Placebo capsules will be administered at the same schedule as Venlafaxine ER. Part two: Open label fo CONDITION: Depression ; Mental and Behavioural Disorders ; Resistant depressive disorder INCLUSION CRITERIA: 1. Patients suffering from major depressive disorder (recurrent or single episode) diagnosed according to Diagnostic and Statistical Manual of the American Psychiatric Association‐IV. revision criteria, confirmed using The Mini‐International Neuropsychiatric Interview ‐ M.I.N.I., Czech version 5.0.0 2. Patients fulfilling at least Stage I criteria for resistant depression according to Thase and Rush (=1 previous, unsuccessful, adequate, antidepressant treatment) 3. The mental ability to understand and sign Informed Consent Form 4. The score in the Montgomery and Åsberg Rating Scale (MADRS) =25 and the score in Clinical Global Impression =4 5. Inpatients in the double‐blind phase of treatment 6. Age between 18 and 65 years 7. Right handedness PRIMARY OUTCOME: Double‐blind study:; 1. Response to treatment with both interventions measured as =50% reduction of MADRS (Montgomery and Åsberg Rating Scale) score at the end of the study (week 4); 2. The number of participants who drop‐out from the study for any reason in either study group during the duration of the study; 3.The ratio of occurrence of a priory defined predictor (reduction of prefrontal cordance value) in responders and non‐responders to both interventions measured after the first week of treatment; ; Open‐label, follow‐up study:; The number of patients suffering from relapse of depression defined as the score =20 points in the MADRS in combination with score 4 or more points in the CGI at the time of follow‐up visits or need of change of antidepressant treatment due to substantial worsening of clinical status during the duration of the open‐label follow‐up study (8 weeks); SECONDARY OUTCOME: Double‐blind study: ; 1. Remission rate for both interventions measured as MADRS score =10 points at the end of the study (week 4); 2.The distribution of current density and its change measured by sLORETA (low resolution electromagnetic tomography) and the analysis of functional connectivity measured by eLORETA (exact low resolution brain electromagnetic tomography) in responders and non‐responders to both interventions at baseline, week 1 and the end of the study (week 4); 3. Functional connectivity in rsfMRI in responders and non‐responders to both interventions (tDCS, venlafaxine) and its change measured at baseline and week 4 of the study; ; Open‐label, follow‐up study:; 1. The distribution of current density measured by sLORETA (low resolution electromagnetic tomography) and the analysis of functional connectivity measured by eLORETA (exact low resolution brain electromagnetic tomography) in participants of the open‐label, follow‐up study (responders in the double‐blind study) treated with both interventions at the beginning and the end of the study