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Microglia have recently been highlighted to understand the pathophysiology of various psychiatric disorders including depression. In this brief review article, we have shown up-to-date knowledge about the effects of psychotropic drugs, especially aripiprazole, on microglial modulation and the relationship between microglia and neurotransmitters such as serotonin and noradrenaline, to understand the cross talk between microglia and neuronal systems. Finally, we have introduced a novel translational research tool, induced microglia-like (iMG) cells from human peripheral blood (monocytes). Further translational studies combining human tissue studies and animal experiences are needed to dig up the microglial roles in the underlying biological mechanisms of depression and other psychiatric disorders.

Schizophrenia is one of the most severe psychiatric diseases noted for its chronic and often debilitating processes; affecting approximately 1% of the worlds population, while its etiology and therapeutic strategies still remain elusive. In the 1950s, the discovery of antipsychotic effects of haloperidol and chlorpromazine shifted the paradigm of schizophrenia. These drugs proved to be antagonists of dopamine D2 receptor (D2R), thus dopamine system dysfunction came to be hypothesized in the pathophysiology of schizophrenia, and D2R antagonism against dopamine neurons has been considered as the primary therapeutic target for schizophrenia. In addition, abnormalities of glutamatergic neurons have been indicated in the pathophysiology of schizophrenia. On the other hand, recent neuroimaging studies have shown that not only dementia but also schizophrenic patients have a significant volume reduction of some specific regions in the brain, which indicates that schizophrenia may involve some neurodegenerative process. Microglia, major sources of various inflammatory cytokines and free radicals such as superoxide and nitric oxide (NO) in the CNS, play a crucial role in a variety of neurodegenerative diseases such as dementia. Recent postmortem and positron emission computed tomography (PET) studies have indicated that activated microglia may be present in schizophrenic patients. Recent in vitro studies have suggested the anti-inflammatory effects of antipsychotics on microglial activation. In this article, we review the anti-inflammatory effects of antipsychotics on microglia, and propose a novel therapeutic hypothesis of schizophrenia from the perspective of microglial modulation.

We herein report a case of Capgras' syndrome observed in interictal psychosis in which the single-photon emission computed tomography (SPECT) findings before and after the appearance of the psychotic symptoms differed. SPECT with 99mTc-hexamethyl propyleneamine oxine (HMPAO) revealed worsening of hypoperfusion in the entire right hemisphere after onset of the psychotic symptoms. The enhanced hypoperfusion demonstrated by SPECT in the present case seems to indicate a right interhemispheric disconnection resulting in the occurrence of Capgras' syndrome.

Maladaptive social interaction and its related psychopathology have been highlighted in psychiatry especially among younger generations. In Japan, novel expressive forms of psychiatric phenomena such as “modern-type depression” and “hikikomori” (a syndrome of severe social withdrawal lasting for at least six months) have been reported especially among young people. Economic games such as the trust game have been utilized to evaluate real-world interpersonal relationships as a novel candidate for psychiatric evaluations. To investigate the relationship between trusting behaviors and various psychometric scales, we conducted a trust game experiment with eighty-one Japanese university students as a pilot study. Participants made a risky financial decision about whether to trust each of 40 photographed partners. Participants then answered a set of questionnaires with seven scales including the Lubben Social Network Scale (LSNS)-6 and the Patient Health Questionnaire (PHQ)-9. Consistent with previous research, male participants trusted partners more than female participants. Regression analysis revealed that LSNS-family (perceived support from family) for male participants, and item 8 of PHQ-9 (subjective agitation and/or retardation) for female participants were associated with participants’ trusting behaviors. Consistent with claims by social scientists, our data suggest that, for males, support from family was negatively associated with cooperative behavior toward non-family members. Females with higher subjective agitation (and/or retardation) gave less money toward males and high attractive females, but not toward low attractive females in interpersonal relationships. We believe that our data indicate the possible impact of economic games in psychiatric research and clinical practice, and validation in clinical samples including modern-type depression and hikikomori should be investigated.

A 69-year-old woman with no family history of mental or neurologic diseases or hypoxic episodes began to show gradual progressive apathy and difficulties in household work at about 50 years of age, followed by emotional blunting. At 68 years of age, she developed catatonia-like signs with little or no spontaneous movement, mutism, and refusal to eat or drink. Frontotemporal dementia (FTD) was suspected because of the bilateral frontal and temporal atrophy shown by an MRI study. At that time, her family found that her symptoms were temporarily resolved with zolpidem without sleepiness. Medical examinations, including a complete blood cell count, and liver, renal, and thyroid function tests, showed no abnormalities. EEG showed dominant α rhythm with occasional slow waves, without any evidence of disturbance of consciousness. Psychotropic agents including zopiclone, lorazepam, brotizolam, alprazolam, diazepam, quazepam, quetiapine, fluvoxamine, lamotrigine, mirtazapine, and amantadine did not resolve her catatonia-like signs. No psychological tests could be performed because of her catatonic state. About 30 minutes after the oral administration of zolpidem (5 mg), her catatonia-like signs gradually ameliorated, and the effect lasted for a few hours. Psychological tests following zolpidem administration demonstrated that her Mini-Mental State Examination score was 21/30, showing disturbances in orientation, attention, and calculation, while the Frontal Assessment Battery score was 11/18 with signs of perseveration that indicated the hypofunction of the frontal lobe. The Bush-Francis Catatonia Rating Scale score changed from 26 to 3 (table). Brain perfusion scans were performed before and after the administration of zolpidem (figure). In both scans, a severe perfusion decrease was observed in bilateral high-frontal lobes, and a mild decrease was observed in bilateral temporal lobes, which was compatible with FTD. After the oral administration of zolpidem, the perfusion was decreased in the brainstem and improved in the thalamus and some cortical areas, including the left parieto-temporal lobe and left cerebellar cortex. The anticatatonic effect of zolpidem has been observed for these 2 years without any side effect.

Recent imaging studies have indicated that the pathophysiology of schizophrenia is closely related to white matter abnormalities and microglial activation. Additionally, recent clinical trials have suggested that atypical antipsychotics may have brain protective properties and that minocycline, an antibiotic with inhibitory effects on microglial activation, improves symptoms of schizophrenia. We have reported that not only atypical antipsychotics with dopamine D2 receptor (D2R) antagonism but also aripiprazole, a unique antipsychotic drug with D2R partial agonism, inhibit microglial activation in vitro. Thus, atypical antipsychotics may exert a beneficial influence on both microglia and oligodendrocytes, while the underlying mechanisms have not been clarified. Here, we investigated whether antipsychotics suppress oligodendrocyte damage by inhibiting microglial activation utilizing a co-culture model with microglia and oligodendrocytes. Pretreatment of aripiprazole and minocycline suppressed apoptosis of oligodendrocytes in the co-culture model with interferon-γ (IFN-γ)-activated microglia, while haloperidol, a traditional antipsychotic drug, did not. Aripiprazole and minocycline inhibited the production of tumor necrosis factor-alpha (TNF-α) from IFN-γ-activated microglia. Moreover, aripiprazole and minocycline attenuated the phosphorylation of signal transducer and activator of transcription 1 (STAT1) in microglia. Overall, our results suggest that aripiprazole and minocycline may have antipsychotic effects through reducing oligodendrocyte damage caused by microglial activation. These results put forward a novel therapeutic hypothesis in schizophrenia research. Future in vivo studies to confirm the present results should be performed.

Aim Japanese psychiatrists have increasingly reported patients with depression that does not seem to fit the criteria of the ICD-10 and the DSM-IV, and which has recently been called modern type depression (MTD). We explored whether MTD is frequently seen in Japan and also in other countries, and if so, how patients with MTD are diagnosed and treated. Methods The questionnaires, with two case vignettes (traditional type depression (TTD) and MTD), were sent to psychiatrists in Australia, Bangladesh, India, Iran, Japan, Korea, Taiwan, Thailand and the USA. Participants rated their opinions about each case's prevalence in their country, etiology, diagnosis, suicide risk, and treatment using Likert scales. Results Out of 247 responses (123 from Japan and 124 from other countries), two hundred thirty-nine valid responses were received. MTD was recognized in all participating countries, and especially in urban areas. Generally, the factor of personality was regarded as the most probable cause of MTD. Whereas about 90% of Japanese psychiatrists applied the ICD/DSM criteria to TTD, only about 60% applied the criteria to MTD. Conclusion Our results indicate that Japan's MTD seems to be occurring in many other countries, and that the present ICD/DSM criteria may not be sufficient to diagnose MTD. Therefore, it could be an important candidate for a new international diagnostic criterion as a subtype of depression. A clear diagnostic framework and consensus on the interventions to treat MTD would be valuable. Further clinical, psychopathological and international epidemiological studies are needed to confirm our preliminary findings of MTD.

Psychiatric disorders have long and dominantly been regarded to be induced by disturbances of neuronal networks including synapses and neurotransmitters. Thus, the effects of psychotropic drugs such as antipsychotics and antidepressants have been understood to modulate synaptic regulation via receptors and transporters of neurotransmitters such as dopamine and serotonin. Recently, microglia, immunological/inflammatory cells in the brain, have been indicated to have positive links to psychiatric disorders. Positron emission tomography (PET) imaging and postmortem studies have revealed microglial activation in the brain of neuropsychiatric disorders such as schizophrenia, depression and autism. Animal models of neuropsychiatric disorders have revealed the underlying microglial pathologies. In addition, various psychotropic drugs have been suggested to have direct effects on microglia. Until now, the relationship between microglia, neurotransmitters and psychiatric disorders has not been well understood. Therefore, in this review, at first, we summarize recent findings of interaction between microglia and neurotransmitters such as dopamine, serotonin, norepinephrine, acetylcholine and glutamate. Next, we introduce up-to-date knowledge of the effects of psychotropic drugs such as antipsychotics, antidepressants and antiepileptics on microglial modulation. Finally, we propose the possibility that modulating microglia may be a key target in the treatment of various psychiatric disorders. Further investigations and clinical trials should be conducted to clarify this perspective, using animal in vivo studies and imaging studies with human subjects.