Polyunsaturated fatty acid (PUFA) metabolism abnormalities have been long implicated in the etiology of schizophrenia. Although several randomized clinical trials have been carried out to assess the efficacy of omega-3 PUFA as add-on therapy in reducing psychopathology in populations of chronic patients with schizophrenia, only a few concern first-episode schizophrenia. The majority of these studies used a 12-week intervention based on ethyl-eicosapentaenoic acid (ethyl-EPA), however, with conflicting results. An intervention based on docosahexaenoic acid plus EPA has not been used in first-episode schizophrenia studies so far. No add-on supplementation studies have been carried out in medicated first-episode schizophrenia patients to assess the efficacy of omega-3 PUFA in preventing relapses. A randomized placebo-controlled one-center trial will be used to compare the efficacy of 26-week intervention, composed of either 1320 mg/day of EPA and 880 mg/day of DHA, or olive oil placebo with regard to symptom severity and relapse rate in first-episode schizophrenia patients. Eighty-two patients (aged 16–35) will be recruited for the study. Eligible patients will be randomly allocated to one of two intervention arms: an active arm or a placebo arm (olive oil). The primary outcome measure of the clinical evaluation is schizophrenia symptom severity measured by the Positive and Negative Syndrome Scale (PANSS). Other outcomes include depressive symptoms, patient functioning and the level of insight. Correlates of change measured during the study will include structural brain changes, oxidative stress and defense, as well as neuroplasticity indicators. Metabolic syndrome components will also be assessed throughout the study. By comparing 26-week administration of EPA + DHA or (placebo) olive oil as add-on therapy in reducing symptom severity and one-year relapse rate in patients with first episode schizophrenia, it is intended to provide new insights into the efficacy of omega-3 PUFA and correlates of change, and contribute to the improvement of mental health care for individuals suffering from schizophrenia. This study has been registered at Clinical Trials.gov with the following number: NCT02210962 .

Rationale N−3 polyunsaturated fatty acids (n−3 PUFA) influence multiple biochemical mechanisms postulated in the pathogenesis of schizophrenia that may influence BDNF synthesis. Objectives A randomized placebo-controlled study was designed to compare the efficacy of a 26-week intervention composed of either 2.2 g/day of n−3 PUFA or olive oil placebo, with regard to symptom severity in first-episode schizophrenia patients. The secondary outcome measure of the study was to describe the association between n−3 PUFA clinical effect and changes in peripheral BDNF levels. Methods Seventy-one patients aged 16–35 were enrolled in the study and randomly assigned to the following study arms: 36 to the EPA + DHA group and 35 to the placebo group. Plasma BDNF levels were assessed three times, at baseline and at weeks 8 and 26 of the intervention. BDNF levels were determined in plasma samples using Quantikine Human BDNF ELISA kit. Plasma BDNF level changes were further correlated with changes in the severity of symptoms in different clinical domains. Results A significantly greater increase in plasma BDNF levels was observed in the intervention compared to the placebo group (Cohen’s d = 1.54). Changes of BDNF levels inversely correlated with change in depressive symptoms assessed using the Calgary Depression Rating Scale in Schizophrenia (Pearson’s r = − 0.195; p = 0.018). Conclusions The efficacy of a six-month intervention with n−3 PUFA observed in first-episode schizophrenia may be related to an increase in BDNF levels, which may be triggered by the activation of intracellular signaling pathways including transcription factors such as cAMP-reactive element binding protein.