Phosphodiesterase inhibitors in psychiatric disorders

• Published in: Psychopharmacology 2023-06, Vol.240 (6), p.1201-1219
• Main Authors: Sadeghi, Mohammad Amin, Nassireslami, Ehsan, Yousefi Zoshk, Mojtaba, Hosseini, Yasaman, Abbasian, Kourosh, Chamanara, Mohsen
• Format: Article
• Language: English
• Subjects: Anxiety; Biomedical and Life Sciences; Biomedicine; Bipolar disorder; Care and treatment; Clinical trials; Cyclic AMP response element-binding protein; Drug development; Enzymes; Humans; Inflammation; Intracellular signalling; Mental depression; Mental disorders; Mental Disorders - drug therapy; Mental illness; Neuroinflammatory Diseases; Neuroplasticity; Neurosciences; Oxidative stress; Patient outcomes; Pharmacology/Toxicology; Phosphodiesterase; Phosphodiesterase 4 Inhibitors; Phosphodiesterase inhibitors; Phosphoric Diester Hydrolases - metabolism; Post traumatic stress disorder; Protein kinase A; Psychiatry; Review; Schizophrenia; Schizophrenia - drug therapy
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-023-06361-3

Rationale Challenges in drug development for psychiatric disorders have left much room for the introduction of novel treatments with better therapeutic efficacies and indices. As a result, intense research has focused on identifying new targets for developing such pharmacotherapies. One of these targets may be the phosphodiesterase (PDE) class of enzymes, which play important roles in intracellular signaling. Due to their critical roles in cellular pathways, these enzymes affect diverse neurobiological functions from learning and memory formation to neuroinflammation. Objectives In this paper, we reviewed studies on the use of PDE inhibitors (PDEIs) in preclinical models and clinical trials of psychiatric disorders including depression, anxiety, schizophrenia, post-traumatic stress disorder (PTSD), bipolar disorder (BP), sexual dysfunction, and feeding disorders. Results PDEIs are able to improve symptoms of psychiatric disorders in preclinical models through activating the cAMP-PKA-CREB and cGMP-PKG pathways, attenuating neuroinflammation and oxidative stress, and stimulating neural plasticity. The most promising therapeutic candidates to emerge from these preclinical studies are PDE2 and PDE4 inhibitors for depression and anxiety and PDE1 and PDE10 inhibitors for schizophrenia. Furthermore, PDE3 and 4 inhibitors have shown promising results in clinical trials in patients with depression and schizophrenia. Conclusions Larger and better designed clinical studies of PDEIs in schizophrenia, depression, and anxiety are warranted to facilitate their translation into the clinic. Regarding the other conditions discussed in this review (most notably PTSD and BP), better characterization of the effects of PDEIs in preclinical models is required before clinical studies.