As implied by the etymology of SZ [schizophrenia from the Greek roots skhizein (to split) and phre-n (mind)], various lines of evidence have suggested that SZ is a disease of neural disconnectivity : a failure of proper functional integration within the brain. Consistently, many of SZ-related gene products are involved in the glutamatergic transmission. We previously reported that the dysfunction of DISC, one of the strong SZ susceptible gene, caused a biphasic detrimental effect on glutamatergic synapse : DISC1 knockdown induces an enhanced glutamatergic transmission in a short term, which results in a reduced glutamatergic transmission in the end. Magnetic resonance spectroscopy (MRS) imaging of longitudinal assessment for SZ individuals have indirectly suggested the hyperglutamatergic condition in early phase of SZ in certain neuronal circuits, eventually resulting in hypoglutamatergic condition, the course of which is reminiscence of the biphasic effect of DISC1 dysfunction. The clinical study have also indicated the drastic change in disease manifestations during the course of disease. However, all drugs currently available in the field of psychiatry are designed for all stages of disease progress. In this seminar, I will overview the glutamatergic dysfunction as the pathogenesis/pathophysiology of SZ in the each stage of disease, and discuss about glutamate-related molecules as novel druggable therapeutic targets for each stage of SZ.

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Accumulating evidence suggests that the hypofunction via N-methyl-D-aspartate (NMDA) receptors plays a role in the pathophysiology of schizophrenia. Based on the NMDA receptor hypofunction hypothesis of schizophrenia, the novel therapeutic drugs for schizophrenia have been developing as follows : metabotropic glutamate receptor (mGluR2/3) agonists, D-serine plus D-amino acid oxidase (DAO) inhibitors, glycine transporter (GlyT-1) inhibitors. Furthermore, the second antibiotic drug minocycline is also one of the attractive therapeutic drugs for schizophrenia. Here the author would like to discuss the possibility of these therapeutic drugs for schizophrenia.

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Schizophrenia is a major and debilitating mental disorder that afflicts about 1% of the population worldwide. Despite intensive, multifaceted research, its exact etiology remains quite elusive. One of the prevailing hypotheses is the “neurodevelopmental abnormality” theory, which proposes that some schizophrenics suffer from subtle neurodevelopmental insults during fetal development, for instance, obstetric complications or maternal virus infections, resulting in biological predisposition to schizophrenia that manifest in adolescence or later. Supporting this theory is convincing epidemiological data showing that when pregnant mothers experienced malnutrition or famine (e. g. the Dutch Hunger Winter of 1994-1945 and the Chinese famine of 1959-1961), the risk of schizophrenia in their children increased by two fold. These facts could be considered in the context of DOHaD. The concept of DOHaD is well referenced in the understanding of common adult diseases such as diabetes mellitus and hypertension, but not so in the field of mental disorders. We will attempt to show how the mechanism of DOHaD could contribute at least in part to schizophrenia pathogenesis and how it can be used to develop preventive interventions for schizophrenia.

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We constructed schizophrenia model rat by injection of Poly (I : C) in the maternal period. Animals in the Poly (I : C) treatment group showed a significant memory/cognitive impairment and social dysfunction in each behavioral test and intravenous neural stem cell transplantation suppressed these behavioral abnormalities toward control levels. The transplanted marked neural stem cells were detected in the various brain regions including cingulated cortex, hippocampus and amygdale over 6 months after the intravenous injection. Specifically, we detected the transplanted neural stem cells in hippocampus and amygdale which were positive with GAD protein suggesting the successful differentiation of transplanted cells into GABAergic neurons in these areas. Moreover, it was demonstrated that combined treatment of antipsychotic olanzapine promoted the migration/survival of transplanted neural stem cells in the brain. These results suggest that drug with stem cell transplantation must develop to a possible therapeutic approach for fetal and childhood stress related psychiatric disease such as schizophrenia and fetal alcohol spectrum disorder.

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The biological markers, such as pentosidine, vitamin B6 and genotype of the glyoxalase I (GLO1) are useful for classifying heterogeneous psychotic syndromes in to homogeneous each types, early diagnosis and state of disease stage in schizophrenic patients with enhanced carbonyl stress. Moreover, pyridoxamine, one of the three forms of vitamin B6, which functions as a carbonyl scavenger is expected to become the therapeutic value of schizophrenia, in addition to be effective in the personalized medicine. In this review, our translational research on carbonyl stress was introduced, and the creation of medical treatment, preventive medicine for carbonyl stress and the prospective view towards omics- based medicine was described.

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Neuromodulation is derived from a concept of slow synaptic transmission in the field of neurophysiology. Recently, the term has been used as a therapeutic methodology in clinical medicine. This article reviews history of neuromodulation in clinical psychiatry and then introduces trends of neuromodulation and their future directions. Neuromodulation in clinical psychiatry could be classified into three categories; 1) exogenous and highly-invasive, 2) exogenous and mildly-invasive, and 3) endogenous and non-invasive. Highly-invasive neuromodulation includes seizure induction or neurosurgical procedures, such as electroconvulsive therapy, psychosurgery, and deep brain stimulation. Endogenous neuromodulation, such as cognitive behavioral therapy and neurofeedback, is independent of external stimuli having electromagnetic or neurochemical actions on the central nervous system. It is important to understand merits and demerits of each type of neuromodulation, and to place neuromodulation techniques properly in a treatment algorithm. From a viewpoint of negative history of prefrontal lobotomy and electroconvulsive therapy, neuromodulation must be applied to clinical psychiatry in future, based on the neuroscience and neuroethics.

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Transcranial magnetic stimulation (TMS) is a non- invasive technique for stimulating the cerebral cortex and altering cortical and subcortical activities. High- frequency stimulation (10- 20 Hz) has been shown to enhance cortical excitability, and low- frequency stimulation (1 Hz) to inhibit cortical excitability. There are two different approaches in the treatment of depression using TMS : high- frequency stimulation over the left dorsolateral prefrontal cortex (DLPFC) and low- frequency stimulation over the right DLPFC. Brain imaging studies in depression have revealed hypoactivity in the DLPFC and overactivity in the ventromedial prefrontal cortex (VMPFC) including subcallosal area and orbitofrontal cortex. The results of our studies suggest that treatment response to TMS may be correlated with cerebral blood flow (CBF) in the DLPFC and VMPFC, providing the possibility that low- frequency stimulation over the right DLPFC may inhibit overactivity in the VMPFC and high- frequency stimulation over the left DLPFC may enhance hypoactivity in the DLPFC with improvement of depression.

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Positron emission tomography (PET) has been used to elucidate the mechanism of action of electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS). We measured cerebral blood flow during acute ECT and demonstrated an increase in the midbrain, mesencephalon, basal ganglia, etc, suggesting the importance of the centroencephalic areas for seizure generalization and the therapeutic efficacy of ECT. Ten-30 minutes after the seizure, reduction in the medial prefrontal and anterior cingulate and an increase in the thalamus were found, indicating those areas are also important. With the recent development of various radioligands, several researches on the neurotransmission using PET have been reported. One study showed no change in serotonin 1A receptors after a course of ECT, while another showed a decrease in dopamine D2 receptor binding in the anterior cingulate, which indicate down- regulation of the receptor due to dopamine release. Very recently, a widespread reduction in the 5-HT2 receptor bindings in all cortical areas was reported. On the other hand, increases in the release of dopamine by acute TMS have been shown in animal and human studies, however, no change in dopamine D2 receptor binding and dopamine synthesis in the striatum were found after a TMS treatment course for depression.

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Several transcranial magnetic stimulation (TMS) techniques are able to examine human cortical excitability and intracortical inhibitory/excitatory mechanisms which are assumed to be mediated by neurotransmitters including GABA and acetylcholine. The late part of the cortical silent period is thought to represent GABA-B-receptor-mediated intracortical inhibition in the motor cortex, and was reported to be inversely associated with negative symptoms in schizophrenia and show different responses depending upon antipsychotics. Short interval intra-cortical inhibition (SICI) measured by using paired-pulse TMS is linked to the function of GABA-A-receptor-mediated cortical interneurons. SICI was reported to be disturbed in schizophrenia, and can be a tool to examine the hypothesis of GABA neurotransmission abnormalities in schizophrenia. Short-latency afferent inhibition (SAI) is related mainly to the function of central cholinergic circuits, and is reduced in cholinergic forms of dementia including Alzheimer disease and dementia with Lewy bodies, but is not reduced in non-cholinergic forms of dementia. SAI can be a useful tool to predict effectiveness of cholinergic drugs in treating demented patients.

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Repetitive transcranial magnetic stimulation (rTMS) is a useful method to noninvasively induce excitability changes in the stimulated and its tightly related cortices. The long lasting excitability changes after rTMS are considered as their neuronal synaptic plasticity changes. Recently, the efficacy of rTMS has been studied for neurological disorders, such as Parkinson’s disease (PD). A double blind randomized trial for effectiveness of 5Hz rTMS over the supplementary motor by Parkinson’s Disease Study Group in Japan showed that the rTMS significantly improved UPDRS III. However, the appropriate stimulus parameters (stimulus frequency, intensity, location etc) of rTMS have not been established to induce clinical efficacy. We recently reported a new rTMS method, quatri-pulse magnetic stimulation (QPS). Repeated trains of four monophasic TMS pulses separated by interstimulus intervals of 1.5-100ms were applied over the motor cortex. QPS at short inter-vals (1.5-10ms) potentiated motor evoked potentials (MEPs), whilst QPS at long intervals (30 -100ms) depressed them. QPS can produce bidirectional after-effects depending on the TMS pulse interval, which were compatible with the synaptic plasticity consistent with Bienenstock-Cooper-Munro (BCM) theory. This new rTMS has a possibility to pro-duce more powerful beneficial effects on neurological symptoms.

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