This study will test whether seven days adjunctive administration of a serotonin receptor subtype 4 (5HT4) agonist called PF-04995274 has positive effects on emotional processing and non-emotional cognition in medicated, treatment-resistant depressed patients compared to placebo.

This study uses a double-blind, placebo-controlled, randomised between-groups design to test if adjunctive administration of a serotonin receptor subtype 4 (5HT4) agonist called PF-04995274 has positive effects on emotional processing and neural activity in medicated treatment-resistant depressed patients. Participants are patients who fulfill criteria for current episode of Major Depressive Disorder (MDD) and have shown lack of response to antidepressant treatment, and they will be randomised to receive 7 days treatment with either PF-04995274 (15 mg daily) or a matched placebo. Participants will come for a Screening Visit, a First Dose Visit, and a Research Visit (including measures of emotional processing and non-emotion cognition).

Inclusion Criteria:

• Male or female;
• Aged 18-65 years;
• Willing and able to give informed consent for participation in the study;
• Sufficiently fluent English to understand and complete the tasks;
• Registered with a GP and consents to GP being informed of participation in study;
• Participants need to meet a number of concurrent clinical criteria:
• Current criteria for Major Depressive Disorder [as determined by the Structured Clinical interview for DSM-V (SCID)];
• Failure within the current depressive episode to respond clinically to at least one course of antidepressant therapy, each given at a therapeutic dose for at least four weeks [as determined by use of the MGH Antidepressant Treatment Response Questionnaire (ATRQ)];
• Currently taking an antidepressant, which must be either a Selective Serotonin Reuptake Inhibitor (SSRI) - with the exception of fluoxetine, paroxetine or fluvoxamine - or a Serotonin-norepinephrine reuptake inhibitor (SNRI) ; Participants currently taking excluded medications can be switched to sertraline or citalopram;
• Participants engaging in sex with a risk of pregnancy must agree to use a highly effective method of contraception from Screening Visit until 30 days after receiving study medication treatment, and male participants must not donate sperm.

Exclusion Criteria:

• History of or current DSM-V bipolar disorder, schizophrenia or eating disorders. Participants who fulfil current criteria for other comorbid disorders may still be entered into the study, if, in the opinion of the Investigator, the psychiatric diagnosis will not compromise safety or affect data quality;
• First-degree relative with a diagnosis of Bipolar Disorder type 1;
• Participants currently taking strong cytochrome P450 (CYPs) enzymes inhibitors, such as fluoxetine, paroxetine or fluvoxamine (in order to avoid drug-drug interactions);
• Participants currently taking psychotropic medications which in the opinion of the investigator may interfere with the safety of the participant or the scientific integrity of the study;
• Participants who have previously failed a combination/augmentation therapy (i.e., therapy with the combination of two or more pharmacological agents) for the treatment of depression, which in the opinion of the Investigator may reduce the likelihood of responding;
• Electroconvulsive therapy for the treatment of the current episode of depression;
• Participants undergoing any form of face-to-face structured psychological treatment during the study;
• Clinically significant abnormal values for liver function tests, clinical chemistry, urine drug screen, blood pressure measurement and ECG. A participant with a clinical abnormality or parameters outside the reference range for the population being studied may be included only if the Investigator considers that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures;
• History of stimulant abuse (lifetime; e.g. amphetamine, cocaine), or of alcohol abuse within one year or of alcohol dependence within the lifetime;
• History of, or current medical conditions which in the opinion of the investigator may interfere with the safety of the participant or the scientific integrity of the study, including epilepsy/seizures, brain injury, severe hepatic or renal disease, severe gastro-intestinal problems, Central Nervous System (CNS) tumors, severe neurological problems (like Parkinson's Disease; blackouts requiring hospitalisation);
• Clinically significant risk of suicide;
• Current pregnancy (as determined by urine pregnancy test taken during Screening and First Dose Visits), breastfeeding or planning a pregnancy during the course of the study;
• Participant not willing to use a suitable method of contraception for 30 days after receiving study medication treatment;
• Participants with Body Mass Index (BMI - kg/m2) outside the 18 - 36 range at the Screening Visit;
• Night-shift working or recent travel involving significant change of timezones;
• Excessive caffeine consumption, i.e., consumption higher than 8 cups of standard caffeinated drinks (tea, instant coffee) or higher than 6 cups of stronger coffee or other drinks containing methylxanthines such as coca cola or Red Bull per day;
• Participation in a psychological or medical study involving the use of medication within the last 3 months;
• Previous participation in a study using the same, or similar, emotional processing tasks;
• Smoker > 10 cigarettes per day or similar levels of tobacco consumption in other forms.
• Participant received prescribed medication within 28 days prior to First Dose Visit (apart from their prescribed antidepressant and the contraceptive pill). Participants who have taken prescription medication may still be entered into the study, if, in the opinion of the Investigator, the medication received will not interfere with the study procedures or compromise safety;
• Participant received non-prescription medication, including supplements such as vitamins and herbal supplements within 48 hours prior to First Dose Visit (apart from paracetamol). Participants who have taken non-prescription medication may still be entered into the study, if, in the opinion of the Investigator, the medication received will not interfere with the study procedures or compromise safety;
• Participant with a known hypersensitivity to PF-04995274 or any other serotonergic agents;
• Participant with planned medical treatment within the study period that might interfere with the study procedures;
• Participant who is unlikely to comply with the clinical study protocol or is unsuitable for any other reason, in the opinion of the Investigator.