Cannabidiol as an add-on therapy to overcome the slow-onset and, possibly, resistance to antidepressant treatment: involvement of NAPE-PLD in the medial prefrontal cortex

Antidepressants such as serotonin uptake inhibitors are the first-line pharmacological treatment for chronic stress-related psychiatric disorders. However, their late-onset therapeutic action and frequent side effects, however, are important challenges for clinicians and patients. Besides, around 30% of major depression patients are considered treatment-resistant. Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid with a wide range of psychopharmacological effects, but its mechanism of action remains unclear. Here, we found that in male mice submitted to two different repeated stress protocols (chronic unpredictable and social defeat stress), low doses of CBD (7.5mg/Kg) caused an early-onset behavioral effect when combined to the antidepressant escitalopram (ESC-10mg/Kg). The behavioral effects of the ESC+CBD combination depended on the expression/activity of the N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD, responsible for synthesizing the endocannabinoid anandamide), but not the DAGL, enzyme in the ventromedial prefrontal cortex. In addition, we described a case series with three treatment-resistant depression that were successfully treated with CBD as adjuvant therapy, as evaluated by standardized clinical rating scales. After 12 weeks of treatment, two patients were considered depression remitted (MADRS score lower than 10) while one patient successfully responded to CBD as add-on treatment (more than 50% decrease from the baseline MADRS). Our results suggest that CBD might be useful as an add-on therapy for optimizing the action of antidepressants. They also suggest that CBDs beneficial actions depends on the facilitation of N-acylethanolamines actions in the medial prefrontal cortex. HighlightsO_LIIn mice, cannabidiol (CBD), but not escitalopram, induced a fast-onset anti-stress action. C_LIO_LICombinations of sub-effective doses of CBD and escitalopram produce anti-stress effects after only 7 days. C_LIO_LIThe Escitalopram + CBD treatment modulated synaptic protein markers in the medial prefrontal cortex. C_LIO_LICRISPR-Cas9-mediated knockdown of NAPE-PLD in the medial PFC prevents the anti-stress effect of the Escitalopram + CBD. C_LIO_LIAdding CBD to an antidepressants regimen successfully treated three patients with treatment resistant depression. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/441143v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@fe2228org.highwire.dtl.DTLVardef@749ec3org.highwire.dtl.DTLVardef@6346b4org.highwire.dtl.DTLVardef@1b6ffbb_HPS_FORMAT_FIGEXP M_FIG C_FIG