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Phosphodiesterase inhibitors in psychiatric disorders

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Psychopharmacology Aims and scope Submit manuscript

Abstract

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.

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Abbreviations

BCCAO:

bilateral common carotid artery occlusion

BP:

bipolar disorder

CAR:

conditioned avoidance response

CR:

conditioned response

CRE:

cAMP-response element

CREB:

cAMP-response element–binding protein

CS:

conditioned stimulus

CUS:

chronic unpredictable stress

DCX:

doublecortin

DISC1:

disrupted in schizophrenia-1

ED:

erectile dysfunction

ERP:

event-related potential

FST:

forced swim test

GC:

guanylyl cyclase

GSK-3β:

glycogen synthase kinase-3β

ID/ED:

intradimensional/extradimensional

IL-1β:

interleukin-1β

JNK:

c-Jun N-terminal kinase

LI:

latent inhibition

LPS:

lipopolysaccharide

LTP:

long-term potentiation

MAP-2:

microtubule-associated protein 2

MDD:

major depressive disorder

NLRP3:

nucleotide-binding domain (NOD)-like receptor protein 3

P38:

p38-mitogen-activated protein kinase

PCP:

phencyclidine

PDE:

phosphodiesterase

PDEI:

phosphodiesterase inhibitor

PKA:

cAMP-dependent protein kinase

PKG:

cGMP-dependent protein kinase

PPI:

prepulse inhibition

PSD95:

postsynaptic protein density 95

PTSD:

post-traumatic stress disorder

RAGE:

receptor for advanced glycation end products

ROS:

reactive oxygen species

SIMA:

stimulant-induced motor activity

SNP:

single nucleotide polymorphism

SPS:

single prolonged stress

SPT:

sucrose preference test

TLR4:

toll-like receptor 4

TST:

tail suspension test

US:

unconditioned stimulus

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Authors and Affiliations

  1. Toxicology Research Center, AJA University of Medical Sciences, Tehran, Iran

    Mohammad Amin Sadeghi, Ehsan Nassireslami & Mohsen Chamanara

  2. Department of Pharmacology, School of Medicine, AJA University of Medical Sciences, Tehran, Iran

    Mohammad Amin Sadeghi, Ehsan Nassireslami & Mohsen Chamanara

  3. Trauma Research Center, AJA University of Medical Sciences, Tehran, Iran

    Mojtaba Yousefi Zoshk

  4. Department of Pediatrics, AJA University of Medical Sciences, Tehran, Iran

    Mojtaba Yousefi Zoshk

  5. Cognitive Neuroscience Center, School of Medicine, AJA University of Medical Sciences, Tehran, Iran

    Yasaman Hosseini

  6. Management and Health Economics Department, AJA University of Medical Sciences, Tehran, Iran

    Kourosh Abbasian

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Sadeghi, M.A., Nassireslami, E., Yousefi Zoshk, M. et al. Phosphodiesterase inhibitors in psychiatric disorders. Psychopharmacology 240, 1201–1219 (2023). https://doi.org/10.1007/s00213-023-06361-3

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