PF-04995274 and Emotional Processing in Treatment Resistant Depression

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 StructuredClinical interview for DSM-V (SCID)];
• Failure within the current depressive episode to respond clinically to at least onecourse of antidepressant therapy, each given at a therapeutic dose for at least fourweeks [as determined by use of the MGH Antidepressant Treatment Response Questionnaire (ATRQ)];
• Currently taking an antidepressant, which must be either a Selective SerotoninReuptake Inhibitor (SSRI) - with the exception of fluoxetine, paroxetine orfluvoxamine - or a Serotonin-norepinephrine reuptake inhibitor (SNRI) ; Participantscurrently taking excluded medications can be switched to sertraline or citalopram;
• Participants engaging in sex with a risk of pregnancy must agree to use a highlyeffective method of contraception from Screening Visit until 30 days after receivingstudy 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 beentered into the study, if, in the opinion of the Investigator, the psychiatricdiagnosis 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, suchas fluoxetine, paroxetine or fluvoxamine (in order to avoid drug-drug interactions);
• Participants currently taking psychotropic medications which in the opinion of theinvestigator may interfere with the safety of the participant or the scientificintegrity 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 treatmentof depression, which in the opinion of the Investigator may reduce the likelihood ofresponding;
• Electroconvulsive therapy for the treatment of the current episode of depression;
• Participants undergoing any form of face-to-face structured psychological treatmentduring the study;
• Clinically significant abnormal values for liver function tests, clinical chemistry,urine drug screen, blood pressure measurement and ECG. A participant with a clinicalabnormality or parameters outside the reference range for the population being studiedmay be included only if the Investigator considers that the finding is unlikely tointroduce additional risk factors and will not interfere with the study procedures;
• History of stimulant abuse (lifetime; e.g. amphetamine, cocaine), or of alcohol abusewithin one year or of alcohol dependence within the lifetime;
• History of, or current medical conditions which in the opinion of the investigator mayinterfere with the safety of the participant or the scientific integrity of the study,including epilepsy/seizures, brain injury, severe hepatic or renal disease, severegastro-intestinal problems, Central Nervous System (CNS) tumors, severe neurologicalproblems (like Parkinson's Disease; blackouts requiring hospitalisation);
• Clinically significant risk of suicide;
• Current pregnancy (as determined by urine pregnancy test taken during Screening andFirst Dose Visits), breastfeeding or planning a pregnancy during the course of thestudy;
• Participant not willing to use a suitable method of contraception for 30 days afterreceiving study medication treatment;
• Participants with Body Mass Index (BMI - kg/m2) outside the 18 - 36 range at theScreening Visit;
• Night-shift working or recent travel involving significant change of timezones;
• Excessive caffeine consumption, i.e., consumption higher than 8 cups of standardcaffeinated drinks (tea, instant coffee) or higher than 6 cups of stronger coffee orother drinks containing methylxanthines such as coca cola or Red Bull per day;
• Participation in a psychological or medical study involving the use of medicationwithin the last 3 months;
• Previous participation in a study using the same, or similar, emotional processingtasks;
• Smoker > 10 cigarettes per day or similar levels of tobacco consumption in otherforms.
• Participant received prescribed medication within 28 days prior to First Dose Visit (apart from their prescribed antidepressant and the contraceptive pill). Participantswho have taken prescription medication may still be entered into the study, if, in theopinion of the Investigator, the medication received will not interfere with the studyprocedures or compromise safety;
• Participant received non-prescription medication, including supplements such asvitamins and herbal supplements within 48 hours prior to First Dose Visit (apart fromparacetamol). Participants who have taken non-prescription medication may still beentered into the study, if, in the opinion of the Investigator, the medicationreceived will not interfere with the study procedures or compromise safety;
• Participant with a known hypersensitivity to PF-04995274 or any other serotonergicagents;
• Participant with planned medical treatment within the study period that mightinterfere with the study procedures;
• Participant who is unlikely to comply with the clinical study protocol or isunsuitable for any other reason, in the opinion of the Investigator.