Major Depression is often resistant to treatment, and all of the currently marketed
anti-depressants can cause significant side effects and may precipitate mania. The aim of
this proposal is to perform a proof-of-concept RCT testing Palmitoylethanolamide (PEA) as a
treatment for unipolar or bipolar depression, randomizing 100 patients to 6-week treatment
with PEA 1200 mg/d or matching placebo. There are several rationales for this study: (A) PEA
acts at the peroxisome proliferator-activated receptor-alpha (PPAR-α), stimulating Allo
biosynthesis. Allo is an endogenous, positive allosteric modulator of GABA-A receptors in
glutamatergic neurons, including cortical and hippocampal pyramidal glutamatergic neurons and
may be one of the endogenous regulators of depression and anxiety. (B) Sage Therapeutics has
developed Allo which is FDA approved to treat post-partum depression, and is testing a
molecular modification which can be administered orally for post-partum depression and
unipolar depression, with mixed efficacy results. Pregnenolone, a precursor of neurosteroids,
has also been reported to improve bipolar depression. Based on animal models, PEA increases
Allo synthesis in areas of the brain thought to be involved in anxiety and depression. It may
also favor the biosynthesis of sulfated forms of Allo and congeners that inhibit tonic rather
than phasic NMDA-mediated excitatory neurotransmission. Showing that PEA-induced selective
inhibition of tonic NMDA neurotransmission improves depression might enable development of
steroid-based NMDA-inhibitor therapeutics. In addition, PEA-induced Allo upregulation
potentiates GABA-A receptor-mediated inhibition. The NMDA and the GABAergic mechanisms may
act in concert to improve behavioral outcomes. Since PEA increases Allo in the brain where it
is endogenously formed, it might be more effective compared with exogenous administration,
which is not site specific. There is evidence of a role of inflammation in depression; PEA
has potent immunoregulatory and anti-inflammatory effects by directly activating PPAR-α,
which has a protective role against neuroinflammation by inhibiting the signaling mediated by
toll-like receptor 4.There is one published study which shows that PEA has an antidepressant
effect in unipolar depression, 58 patients were randomized to receive 1200 mg/d of PEA or
placebo added-on to citalopram, showing clinical improvements in patients receiving PEA.