PDE4A and major depressive disorder: Early clinical trials with rolipram demonstrated encouraging antidepressant effects in patients with major depressive disorder, while low dose roflumilast, a second-generation PDE4 inhibitor, has been shown to improve verbal and working memory in individuals with schizophrenia and healthy older adults (Zeller et al., 1984; Gilleen et al., 2021; Blokland et al., 2019b).