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

摘要: 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, important challenges clinicians patients. Besides, around 30% of major depression patients considered treatment-resistant. Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid with wide range psychopharmacological but its mechanism remains unclear. Here, we found that in male mice submitted to two different repeated stress protocols (chronic unpredictable social defeat stress), low doses CBD (7.5mg/Kg) caused an early-onset behavioral effect when combined antidepressant escitalopram (ESC-10mg/Kg). The effects ESC+CBD combination depended on expression/activity N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD, responsible synthesizing endocannabinoid anandamide), not DAGL, enzyme ventromedial prefrontal cortex. In addition, described case series three treatment-resistant were successfully treated adjuvant therapy, evaluated by standardized clinical rating scales. After 12 weeks treatment, remitted (MADRS score lower than 10) while one patient responded add-on (more 50% decrease from baseline MADRS). Our results suggest might be useful therapy optimizing antidepressants. They also CBDs beneficial actions depends facilitation N-acylethanolamines medial HighlightsO_LIIn mice, cannabidiol (CBD), escitalopram, induced fast-onset anti-stress action. C_LIO_LICombinations sub-effective produce after only 7 days. C_LIO_LIThe Escitalopram + modulated synaptic protein markers C_LIO_LICRISPR-Cas9-mediated knockdown NAPE-PLD PFC prevents CBD. C_LIO_LIAdding antidepressants regimen 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