Signed informed consent
Male or female
Age 18‐65 years inclusive
Particpants with a current episode of moderate to severe Major Depressive Disorder meeting the criteria of Diagnostic and Statistical Manual of Mental Disorders (DSM) IV ‐TR and documented using the brief structured interview Mini International Neuropsychiatric Interview (MINI) version 5.0 and with a minimum duration of two weeks and a maximum of 12 months
Minimum HRSD‐17 items total score of 18 at screening and ≥12 at the end of the lead‐in phase prior to randomisation
Male participants with female partners of child‐bearing potential and female participants who are neither surgically sterilised nor post‐menopausal (defined as no menses for one year or an follicle stimulating hormone (FSH) value >40 IU/L) will be required to use effective contraception throughout the study and for 30 days after. The following contraceptive methods are acceptable: hormonal (e.g. oral, injection, transdermal patch, implant, cervical ring), barrier (e.g. condom or diaphragm with spermicidal agent), intrauterine system (IUS) or intrauterine device (IUD). If hormonal contraceptives are used by female participants they must be established for 6 weeks before the first administration of test product. Male sterilisation is considered an acceptable form of contraception if the appropriate post‐vasectomy documentation (absence of sperm) is provided. Sexual abstinence is considered acceptable if this is in line with the preferred and usual lifestyle of the participant; periodic abstinence (e.g., calendar, ovulation, symptothermal, post‐ovulation methods) and withdrawal are not acceptable methods of contraception
Able to understand and comply with the requirements of the study as judged by the investigator
Considered by the investigator to be at significant risk of suicide or scoring 5 or more on the Montgomery Asberg Depression Rating Scale (c) question 10
Significant other psychiatric illness which would interfere with trial assessments comorbid generalised anxiety disorder (GAD) and panic disorder will be permitted where MDD is considered the primary diagnosis
Significant physical illness which would interfere with trial assessments
Recent (within 1 week of screening) antidepressants (except for fluoxetine [within 4 weeks of screening] and St John's Wort or Monoamine oxidase inhibitors (MAOI) [within 14 days of screening])
Benzodiazepine or any other psychotropic medication including lithium or other mood stabilisers within 1 week of screening
Oral anticoagulant therapy within one month of screening
Formal psychotherapy or alternative treatments for one week prior to screening or during the study
Reduced hepatic function defined as liver enzyme levels ≥ 2.5 times upper limit of normal
Renal insufficiency defined as creatinine clearance < 30 mL/min
Epilepsy
Uncontrolled hypothyroidism
Uncontrolled hypertension
Acute porphyria
Urinary retention, prostatic hypertrophy, narrow angle glaucoma or increased intraocular pressure or any other clinically relevant contraindication stated in the Summary of Product Characteristics (SmPC) for citalopram, tramadol or amitriptyline
History of significant cardiac dysrhythmia or history of myocardial infarction within 1 year prior to screening
Significant history of alcohol or substance abuse
Regular alcohol intake above the recommended United Kingdom (UK) guideline of 4 units per day for males or 3 units per day for females
Pregnant or lactating women
Known hepatitis B or C or human immunodeficiency virus (HIV) or syphilis seropositivity.
A corrected QT interval of > 470 ms for female participants of > 450 ms for male participants, calculated using the QTcB (Bazett Correction Formula) , or second degree or higher heart block on an electrocardiography (ECG) recording, at screening.
Allergy to the study drugs or excipients
Treatment with another investigational medicinal product within the 30 days prior to screening
