Enhancement of memory network activity in schizophrenia patients by phosphodiesterase-4 (PDE4) inhibitor, roflumilast: A pilot study

BACKGROUND: Cognitive impairments are prevalent in schizophrenia and are associated with functional outcomes, yet there are currently no approved treatments to address these deficits. Roflumilast, a phosphodiesterase 4 inhibitor, has previously been shown to improve verbal memory in healthy and schizophrenia populations. AIMS: This study aimed to investigate the neural changes which occur with roflumilast administration and which may underpin these cognitive effects. METHODS: Ten participants with schizophrenia were administered 8 days of placebo, 100 and 250 µg of roflumilast in a 3-way crossover design. We present analyses of seed-based functional connectivity (FC) with bilateral hippocampus (HC) and regional cerebral blood flow measured with arterial spin labelling. RESULTS: Results indicated that 250 µg roflumilast was associated with significantly greater FC between HC and prefrontal cortex (PFC) compared to placebo. There was also a significant increase in cerebral blood flow with 250 µg roflumilast relative to placebo in the dorsolateral PFC and HC. CONCLUSIONS: These changes provide preliminary support for a cerebral mechanism of action of roflumilast, which includes modulation of brain regions involved in memory known to be impaired in patients with schizophrenia. This data supports existing findings suggesting roflumilast has the potential to be an effective treatment for cognitive impairments in schizophrenia.