PEA vs. Placebo for Major Depression

This is a multi-center, 6-week, randomized, double blind, placebo-controlled clinical trial of PEA vs. placebo in patients with unipolar or bipolar disorder who are currently in a Major Depressive Episode (MDE). PEA or placebo will be administered as monotherapy and any antidepressant, mood stabilizer or antipsychotic medication will be tapered down starting from the randomization day. The tapering process will be of one week, except for fluoxetine which will be tapered for a duration of two weeks. At the screening visit, after signing the informed consent form, patients will be assessed using the MINI. MADRS and YMRS will be assessed for inclusion/exclusion criteria. Demographic information will be collected, psychiatric and medical history obtained, physical examination including height and weight, blood pressure and pulse rate will be performed. Blood samples for biochemistry analyses and CBC, and urine samples for urinalysis will be taken. Females of child-bearing potential will be tested for pregnancy. An ECG will be performed. Blood for neurosteroids and other biomarkers will be taken, processed to separate plasma from PBMC and stored, to be sent later to the laboratory of Dr. Pinna. The baseline visit will be performed up to 7 days after screening. MADRS, CGI-BP/CGI-D, HAM-A and HAM-D will be collected. The use of concomitant medications as well as Adverse Events will be recorded throughout the study. Patients will be randomized to start study medication. The clinical questionnaires will be administered 2, 4 and 6 (End-of study, EOS) weeks after baseline. Biomarker analyses, including plasma neurosteroid and BDNF levels will be measured at baseline, and at the week 6 (EOS) visit. Concomitant medications and adverse events, as well as any other clinical change will be monitored through phone visits which will take place twice weekly on weeks 1, 3 and 5. Study medication will be manufactured by Innexus Nutraceuticals in the Netherlands according to GMP, and will then be sent to Micronisierungs-Kontor Oberrot GmbH in Germany for micronization. The micronized compound will then be sent to PharmaMed Inc. in Pennsylvania, USA for packaging and labelling. Study medication will be randomized according to a computerized list supplied by the investigators to Innexus Nutraceuticals and PharmaMed Inc. Randomization of patients will be sequential. Kits will be kept in one central site, and after randomization patients from other site will be supplied with the kits. Concomitant medication: After the screening visit, patients will start a tapering process for all antidepressant/antipsychotic/mood stabilizer. The tapering process will be of one week, except for fluoxetine which will be tapered for a duration of two weeks. Rescue Medication: Up to 3 mg/day of lorazepam will be allowed as rescue medication in case of clinical deterioration, based on clinician's judgment. Laboratory: Quantification of Allo and congeners, and PEA will performed by the state-of-the-art technology, GC-MS. The methodology to determine neurosteroid levels is a technique developed in Dr Pinna's lab (HPLC combined with GC-MS quantification), which allows the simultaneous determination of various neurosteroids from a single sample due to molar sensitivity and unsurpassed structural specificity.