An increase in plasma brain derived neurotrophic factor levels is related to n-3 polyunsaturated fatty acid efficacy in first episode schizophrenia: secondary outcome analysis of the OFFER randomized clinical trial

Psychopharmacology (Berl). 2019 Sep;236(9):2811-2822. doi: 10.1007/s00213-019-05258-4. Epub 2019 May 17.


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.

Keywords: Brain-derived neurotrophic factor; Fatty acid; Neuroprotection; Randomized clinical trial; Supplementation.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Antipsychotic Agents / administration & dosage*
  • Biomarkers / blood
  • Brain-Derived Neurotrophic Factor / blood*
  • Double-Blind Method
  • Fatty Acids, Omega-3 / therapeutic use*
  • Female
  • Humans
  • Male
  • Olive Oil / therapeutic use
  • Psychiatric Status Rating Scales
  • Schizophrenia / blood*
  • Schizophrenia / drug therapy*
  • Schizophrenic Psychology*
  • Treatment Outcome
  • Young Adult


  • Antipsychotic Agents
  • Biomarkers
  • Brain-Derived Neurotrophic Factor
  • Fatty Acids, Omega-3
  • Olive Oil
  • BDNF protein, human