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Rationale One of the major complaints most people face during aging is an impairment in cognitive functioning. This has a negative impact on the quality of daily life and is even more prominent in patients suffering from neurodegenerative and psychiatric disorders including Alzheimer's disease, schizophrenia, and depression. So far, the majority of cognition enhancers are generally targeting one particular neurotransmitter system. However, recently phosphodiesterases (PDEs) have gained increased attention as a potential new target for cognition enhancement. Inhibition of PDEs increases the intracellular availability of the second messengers cGMP and/or cAMP. Objective The aim of this review was to provide an overview of the effects of phosphodiesterase inhibitors (PDE-Is) on cognition, the possible underlying mechanisms, and the relationship to current theories about memory formation. Materials and methodsStudies of the effects of inhibitors of different PDE families (2, 4, 5, 9, and 10) on cognition were reviewed. In addition, studies related to PDE-Is and blood flow, emotional arousal, and long-term potentiation (LTP) were described. Results PDE-Is have a positive effect on several aspects of cognition, including information processing, attention, memory, and executive functioning. At present, these data are likely to be explained in terms of an LTP-related mechanism of action. Conclusion PDE-Is are a promising target for cognition enhancement; the most suitable candidates appear to be PDE2-Is or PDE9-Is. The future for PDE-Is as cognition enhancers lies in the development of isoform-specific PDE-Is that have limited aversive side effects.

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Phosphodiesterase type 5 inhibitors (PDE5-Is) improve cognitive performance of rodents, but the few human studies investigating their effects did not systematically investigate cognitive effects and the results have been quite contradictory. Therefore, we examined whether the PDE5-I vardenafil improves memory and executive functioning and affect electroencephalography (EEG) in healthy young adults. Participants were selected out of a group of volunteers, based on their performance on a memory screening and they were orally treated with vardenafil (10-20 mg or placebo). Memory and executive functioning were tested while EEG activity was recorded. Additionally, a simple reaction time task and questionnaires addressing various complaints were presented. No prominent effects of vardenafil on cognition were found: participants only made more mistakes on a reaction time task after 20 mg vardenafil. During encoding of words, the P300 was generally smaller after vardenafil treatment. Furthermore, the N400 was larger after vardenafil 10 mg than placebo treatment in a spatial memory task at Fz. Finally, headache and feeling weak were reported more after vardenafil treatment. Vardenafil did not affect cognitive performance of healthy adults and showed only some incidental effects on ERPs. These findings in humans do not corroborate the cognition-enhancing effects of PDE5-Is in healthy animals.

No pharmacological treatment is available to date that shows satisfactory effects on cognitive symptoms in patients diagnosed with schizophrenia. Phosphodiesterase inhibitors (PDE-Is) improve neurotransmitter signaling by interfering in intracellular second messenger cascades. By preventing the breakdown of cAMP and/or cGMP, central neurotransmitter activity is maintained. Different PDE families exist with distinct characteristics among which substrate specificity and regional distribution. Preclinical data is promising especially with regard to inhibition of PDE2, PDE4, PDE5 and PDE10. In addition, cognitive improvement has been reported in both elderly and/or non-impaired young human subjects after PDE1 or PDE4 inhibition. Moreover, some of these studies show effects on cognitive domains relevant to schizophrenia, in particular memory. The current review incorporates an overview of the distinct molecular characteristics of the different PDE families and their relationship to the neurobiological mechanisms related to cognitive dysfunction in schizophrenia. So far, procognitive effects of only three types of PDE-Is have been assessed in patients diagnosed with schizophrenia inhibiting PDE3, PDE5 and PDE10. However, the limited data available do not allow to draw firm conclusions on the value of PDE-Is as cognitive enhancers in schizophrenia yet. The field is still in its infancy, but nevertheless different PDE-Is seem promising as candidate to optimise neural communication in the prefrontal cortex favouring cognitive functioning in patients diagnosed with schizophrenia, in particular dual inhibitors including PDE1-Is, PDE3-Is and PDE10A-Is.