Editorial [Hot topic:Novel Potential Therapeutic Approaches for Schizophrenia (Executive Guest Editor: Kenji Hashimoto)]

Schizophrenia is a chronic, severe, and disabling brain disorder that affects about 1 percent of people worldwide. The manifestations of this disorder are positive symptoms (e.g., hallucinations, delusions, racing thoughts), negative symptoms (e.g., apathy, lack of emotion, poor or nonexistent social functioning), and cognitive deficits (e.g., poor executive functioning, trouble focusing or paying attention, problems with working memory). Although current treatments with antipsychotic drugs can eliminate some these symptoms in patients with schizophrenia, these drugs are not effective against negative symptoms and cognitive deficits. Although the precise causes of schizophrenia have not been determined, a number of pharmaceutical companies have been developing novel therapeutic drugs to treat this disorder. In this special issue, a multidisciplinary team of international experts discusses all the most relevant topics on novel therapeutic targets for schizophrenia. Multiple lines of evidence have implicated abnormalities in both glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) and metabotropic glutamate receptors (mGluRs) in the pathophysiology of schizophrenia. In this issue, Chaki and Hikichi (Taisho Pharmaceutical Co., Ltd., Japan) review recent topics in novel mGluR agonists/antagonists as novel potential therapeutic drugs for schizophrenia [1]. Considering the NMDA receptor hypofunction hypothesis for schizophrenia, the NMDA receptor glycine modulatory site is the most attractive therapeutic target for this disorder. Currently, D-serine (an endogenous co-agonist at the glycine modulatory site) and glycine transporter-1 (GlyT-1) inhibitors are considered potential therapeutic drugs for schizophrenia. Although D-amino acids including D-serine and D-alanine have been shown to be effective in the treatment of schizophrenia, these D-amino acids are metabolized by D-amino acid oxidase (DAAO) in the peripheral organs, reducing their bioavailability in the brain. In this issue, Ferraris and Tsukamoto (The Johns Hopkins University, USA) review recent topics in novel DAAO inhibitors as potential therapeutic drugs for schizophrenia [2]. Furthermore, Hashimoto (Chiba University, Japan) reviews recent findings on novel GlyT-1 inhibitors as potential therapeutic drugs [3]. Accumulating evidence suggests that the α7 subtype of nicotinic acetylcholine receptors (α7 nAChRs) plays an important role in the P50 auditory evoked-potential deficits in patients with schizophrenia, and that α7 nAChR agonists would be potential therapeutic drugs for cognitive deficits associated with P50 deficits in schizophrenia. In this issue, Ishikawa and Hashimoto (Chiba University, Japan) review recent topics in ??7 nAChRs in the pathophysiology of schizophrenia and on novel α7 nAChR agonists as potential therapeutic drugs [4]. In contrast, kynurenic acid, a product of the normal metabolism of the amino acid L-tryptophan, is the endogenous antagonist at NMDA receptors as well as at α7 nAChRs. Müller et al. (Ludwig-Maximilians University, Germany) review recent topics in the kynurenic acid pathway in the pathophysiology of schizophrenia [5]. Phosphodiesterase 10A (PDE10A) is a basal ganglia-specific hydrolase that plays an essential role in regulating cAMP/PKA and cGMP/PKG signaling cascades in the brain. Biochemical and behavioral data indicate that PDE10A inhibition activates cAMP/PKA signaling in the basal ganglia, leading to the potentiation of dopamine D1- and adenosine A2A-receptor signaling, with concomitant inhibition of dopamine D2- and adenosine A1-receptor signaling. In this issue, Kehler (Lundbeck A/S, Denmark) reviews novel PDE10A inhibitors as new treatments for schizophrenia [6]....