Treatment of Cognitive Impairment in Schizophrenia: Potential Value of Phosphodiesterase Inhibitors in Prefrontal Dysfunction

Abstract

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.

Cardiac Phosphodiesterases and Their Modulation for Treating Heart Disease

“…PDE9A is the most selective for cGMP from all the 11 species (Fisher et al, 1998; Soderling et al, 1998), and has been clinically developed and tested for its potential to treat cognitive disorders such as Alzheimer’s and schizophrenia (Duinen et al, 2015). It is expressed most prominently in brain (though still at low levels), but also in gut, kidney, and heart.…”

Targeting the dopamine D1 receptor or its downstream signalling by inhibiting phosphodiesterase‐1 improves cognitive performance

“…Accordingly, inhibition of the cyclic nucleotide PDEs that degrade the second messenger molecule cAMP should have a D 1 receptor agonist‐like effect. Because http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=260#1295 is postulated to regulate D 1 receptor‐dependent signal transduction (Duinen et al, 2015; Snyder et al, 2016), this study aimed to elucidate the role of PDE1 in cognitive processes that are believed to depend on prefrontal D 1 receptor function.…”

Phosphodiesterase Inhibition and Regulation of Dopaminergic Frontal and Striatal Functioning: Clinical Implications

“…PDE2A, PDE4 (A, B, D), and PDE9A are more widely distributed but are also expressed in striatum and/or frontal cortex. There are only very limited preclinical data on PDE2A, PDE7A, and PDE9A inhibition (e.g., Duinen et al, 2015). To date, most research has been devoted to the potential of PDE1B, PDE4, and PDE10A for regulation of dopaminergic frontal and striatal signaling, and therefore these subtypes will be discussed below.…”