Microglia and cognitive impairment in schizophrenia: translating scientific progress into novel therapeutic interventions.

Cognitive impairment is a core clinical feature of schizophrenia, exerting profound adverse effects on social functioning and quality of life in a large proportion of patients with schizophrenia. However, the mechanisms underlying the pathogenesis of schizophrenia-related cognitive impairment are not well understood. Microglia, the primary resident macrophages in the brain, have been shown to play important roles in psychiatric disorders, including schizophrenia. Increasing evidence has revealed excessive microglial activation in cognitive deficits related to a broad range of diseases and medical conditions. Relative to that about age-related cognitive deficits, current knowledge about the roles of microglia in cognitive impairment in neuropsychiatric disorders, such as schizophrenia, is limited, and such research is in its infancy. Thus, we conducted this review of the scientific literature with a focus on the role of microglia in schizophrenia-associated cognitive impairment, aiming to gain insight into the roles of microglial activation in the onset and progression of such impairment and to consider how scientific advances could be translated to preventive and therapeutic interventions. Research has demonstrated that microglia, especially those in the gray matter of the brain, are activated in schizophrenia. Upon activation, microglia release key proinflammatory cytokines and free radicals, which are well-recognized neurotoxic factors contributing to cognitive decline. Thus, we propose that the inhibition of microglial activation holds potential for the prevention and treatment of cognitive deficits in patients with schizophrenia. This review identifies potential targets for the development of new treatment strategies and eventually the improvement of care for these patients. It might also help psychologists and clinical investigators in planning future research.

Low-dose lithium adjunct to quetiapine improves cognitive task performance in mice with MK801-induced long-term cognitive impairment: Evidence from a pilot study.

BACKGROUND: Low-dose lithium (LD-Li) has been shown to rescue cognitive impairment in mouse models of short-term mild cognitive impairment, dementia, and schizophrenia. However, few studies have characterized the effects of LD-Li, alone or in conjunction with anti-psychotics, in the mouse model of MK801-induced long term cognitive impairment. METHODS: The present study used in vivo Ca2+ imaging and a battery of cognitive function assessments to investigate the long-term effects of LD-Li on cognition in mice exposed to repeated injections of MK801. Prefrontal Ca2+ activity was visualized to estimate alterations in neural activity in the model mice. Pre-pulse inhibition (PPI), novel object recognition (NOR), Morris water maze (MWM), and fear conditioning (FC) tasks were used to characterize cognitive performance; open field activity (OFA) testing was used to observe psychotic symptoms. Two treatment strategies were tested: LD-Li [250 mg/d human equivalent dose (HED)] adjunct to quetiapine (QTP; 600 mg/d HED); and QTP-monotherapy (mt; 600 mg/d HED). RESULTS: Compared to the QTP-mt group, the LD-Li + QTP group showed greatly improved cognitive performance on all measures between experimental days 29 and 85. QTP-mt improved behavioral measures compared to untreated controls, but the effects persisted only from day 29 to day 43. These data suggest that LD-Li + QTP is superior to QTP-mt for improving long-term cognitive impairments in the MK801 mouse model. LIMITATIONS: There is no medical consensus regarding lithium use in patients with schizophrenia. CONCLUSION: More pre-clinical and clinical studies are needed to further investigate effective treatment strategies for patients with long-term cognitive impairments, such as chronic schizophrenia.

Validity and reliability of a Chinese language suicide screening questionnaire-observer rating (CL-SSQ-OR) assessment for children/adolescents.

Background: A Suicide Screening Questionnaire-Observer Rating (SSQ-OR) has been used to assess risk of suicide among individuals and to help clinicians identify and rescue individuals attempting suicide. To prevent the risk of suicide in China, a Chinese language SSQ-OR (CL-SSQ-OR) needs to be introduced. Objective: To test the validity and reliability of a CL-SSQ-OR. Method: A total of 250 individuals were enrolled in this study. Each completed a CL-SSQ-OR assessment, Patient Health Questionnaire-9, and the Beck Scale for Suicide Ideation. Confirmatory factor analysis (CFA) was adopted to determine structural validity. Spearman correlation coefficients were adopted to determine criterion validity. An internal correlation coefficient (ICC) was used to test inter-consistency and Cronbach's α coefficient was used to test split-half reliability. Results: CFA was conducted with use of the maximum variance method to evaluate the item results. All of the items received scores >0.40. In addition, good model fit indices were observed for the two-factor structure RMSEA = 0.046, TLI = 0.965, CFI = 0.977. The items' factor loading of the CL-SSQ-OR in the first factor ranged from 0.443 to 0.878. The items' factor loading of the CL-SSQ-OR in the second factor ranged from 0.400 to 0.810. The ICC of the total CL-SSQ-OR was 0.855. Cronbach's α was 0.873. Conclusion: The CL-SSQ-OR described here demonstrates ideal psychometric properties and is found to be a suitable tool for screening Chinese children/adolescents who are at risk of suicide.

Low-dose lithium mono- and adjunctive therapies improve MK-801-induced cognitive impairment and schizophrenia-like behavior in mice - Evidence from altered prefrontal lobe Ca2+ activity.

BACKGROUND: Few studies have evaluated lithium either as monotherapy or in combination with anti-psychotic agents to improve cognition in murine models of schizophrenia. METHODS: Visualization of Ca2+ activity in the prefrontal cortex was used to characterize brain neural activity. Novel object recognition (NOR), Morris water maze (MWM), and fear conditioning (FCT) tests were used to characterize cognitive performance; while pre-pulse inhibition (PPI), elevated plus maze (EPM) and the open field test (OFT) were used to characterize schizophrenia-like behavior. RESULTS: A 28-day course of low-dose lithium (human equivalent dose of 250 mg/day) combined with moderate-dose quetiapine (human equivalent dose of 600 mg/day) improved Ca2+ ratio by 70.10 %, PPI by 69.28 %, NOR by 70.09 %, MWM by 71.28 %, FCT by 68.56 %, EPM by 70.95 % and OFT by 75.23 % compared to the results of positive controls. Unexpectedly, moderate-dose lithium (human equivalent dose of 500 mg/day) used either as monotherapy or as an adjunct with quetiapine worsened Ca2+ activity, PPI, MWM, FCT, EPM, and OPT. LIMITATIONS: Our study cannot explain the contrasting positive and negative effects of low-dose and moderate-dose lithium, respectively, when used either as monotherapies or as adjuncts. Further studies, especially Western blotting, may reveal molecular mechanisms of action. CONCLUSIONS: Low-dose lithium (human equivalent dose of 250 mg/day) combined with moderate-dose quetiapine (human equivalent dose of 600 mg/day) provided the best improvements. Furthermore, benefits persisted for 14 days post-treatment. Our data provide directions for further research of therapeutic alternatives to mitigate schizophrenia-related cognopathy.

Risk-to-befit ratios of consecutive antidepressants for heavy menstrual bleeding in young women with bipolar disorder or major depressive disorder.

The occurrence of heavy menstrual bleeding (HMB) induced by pharmacological agents has been reported in young adult women. This study aimed to investigate a possible association between the occurrence rates of HMB and different treatment methods such as antidepressant agents alone and in combination with other pharmacological agents. The examined cohort included young women (age 18-35 years, n = 1,949) with bipolar disorder (BP) or major depressive disorder (MDD). Menstruation history for 24 months was recorded and evaluated according to pictorial blood loss assessment charts of HMB. Multivariate analyses were conducted to determine odds ratios (ORs) and 95% confidence intervals. The examined antidepressant agents had varying ORs for patients with BP vs. those with MDD. For example, the ORs of venlafaxine-induced HMB were 5.27 and 4.58 for patients with BP and MDD, respectively; duloxetine-induced HMB, 4.72 and 3.98; mirtazapine-induced HMB, 3.26 and 2.39; fluvoxamine-induced HMB, 3.11 and 2.08; fluoxetine-induced HMB, 2.45 and 1.13; citalopram-induced HMB, 2.03 and 1.25; escitalopram-induced HMB, 1.85 and 1.99; agomelatine-induced HMB, 1.45 and 2.97; paroxetine-induced HMB, 1.19 and 1.75; sertraline-induced HMB, 0.88 and 1.13; reboxetine-induced HMB, 0.45 and 0.45; and bupropion-induced HMB, 0.33 and 0.37, in each case. However, when antidepressant agents were combined with valproate, the OR of HMB greatly increased, with distinct profiles observed for patients with BP vs. those with MDD. For example, the ORs of HMB induced by venlafaxine combined with valproate were 8.48 and 6.70 for patients with BP and MDD, respectively; for duloxetine, 5.40 and 4.40; mirtazapine, 5.67 and 3.73; fluvoxamine, 5.27 and 3.37; fluoxetine, 3.69 and 4.30; citalopram, 5.88 and 3.46; escitalopram, 6.00 and 7.55; agomelatine, 4.26 and 5.65; paroxetine, 5.24 and 3.25; sertraline, 4.97 and 5.11; reboxetine, 3.54 and 2.19; and bupropion, 4.85 and 3.46, in each case. In conclusion, some antidepressant agents exhibited potential risks of inducing HMB. Therefore, a combined prescription of antidepressant agents and valproate should be carefully considered for young women with HMB.

Higher benefit-risk ratio of COVID-19 vaccination in patients with schizophrenia and major depressive disorder versus patients with bipolar disorder when compared to controls.

Patients with major psychiatric disorders (MPD) that include schizophrenia (SCH), bipolar disorder (BP), and major depressive disorder (MDD) are at increased risk for coronavirus disease 2019 (COVID-19). However, the safety and efficacy of COVID-19 vaccines in MPD patients have not been fully evaluated. This study aimed to investigate adverse events (AEs)/side effects and efficacy of COVID-19 vaccines in MPD patients. This retrospective study included 2034 patients with SCH, BP, or MDD who voluntarily received either BBIBP-CorV or Sinovac COVID-19 vaccines, and 2034 matched healthy controls. The incidence of AEs/side effects and the efficacy of COIVD-19 vaccinations among the two groups were compared. The risk ratio (RR) of side effects in patients with MPD was 0.60 (95% confidence interval [CI]: 0.53-0.68) after the first dose and 0.80 (95% CI: 0.65-0.99) following the second dose, suggesting a significantly lower risk in the MPD group versus healthy controls. The RRs of AEs did not differ between patients and controls. Notably, fully vaccinated patients exhibited a decreased risk of influenza with or without fever compared with controls (RR=0.38, 95% CI: 0.31-0.46; RR=0.23, 95% CI: 0.17-0.30; respectively). Further subgroup comparisons revealed a significantly lower risk of influenza with fever in MDD (RR=0.13, 95% CI: 0.08-0.21) and SCH (RR=0.24, 95% CI: 0.17-0.34) than BP (RR=0.85, 95% CI: 0.69-1.06) compared to controls. We conclude that the benefit-risk ratio of COVID-19 vaccination was more favorable in SCH or MDD versus BP when compared with controls. These data indicate that COVID-19 vaccines are safe and protective in patients with MPD from COVID-19.

Associations of cognitive impairment in patients with schizophrenia with genetic features and with schizophrenia-related structural and functional brain changes.

Cognitive impairment is highly prevalent in patients with major psychiatric disorders (MPDs), including schizophrenia (SCZ), bipolar disorder, major depressive disorder, in whom it can be highly disruptive to community functioning and worsen prognosis. Previously, genetic factors and cognitive impairments in MPD patients have been examined mostly in isolated circuits rather than in the whole brain. In the present study, genetic, neuroimaging, and psychometric approaches were combined to investigate the relationship among genetic factors, alterations throughout the brain, and cognitive impairments in a large cohort of patients diagnosed with SCZ, with a reference healthy control (HC) group. Single nucleotide polymorphisms (SNPs) in SCZ-risk genes were found to be strongly related to cognitive impairments as well as to gray matter volume (GMV) and functional connectivity (FC) alterations in the SCZ group. Annotating 136 high-ranking SNPs revealed 65 affected genes (including PPP1R16B, GBBR2, PDE4B, CANCNA1C, SLC12AB, SATB2, MAG12, and SATB2). Only one, a PDE4B SNP (rs1006737), correlated with GMV (r = 0:19 p = 0.015) and FC (r = 0.21, p = 0.0074) in SCZ patients. GMV and FC alterations correlated with one another broadly across brain regions. Moreover, the present data demonstrate three-way SNP-FC-GMV associations in patients with SCZ, thus providing clues regarding potential genetic bases of cognition impairments in SCZ. SNP-FC-GMV relationships correlated with visual learning and reasoning dimensions of cognition. These data provide evidence that SCZ-related cognitive impairments may reflect genetically underlain whole-brain structural and functional alterations.

Prevalence of Heavy Menstrual Bleeding and Its Associated Cognitive Risks and Predictive Factors in Women With Severe Mental Disorders.

There has been limited studies examining treatment-induced heavy menstrual bleeding (HMB) in women with severe mental illnesses. The aim of this study was to examine HMB prevalence and HMB-associated factors in young women (18-34 years old) diagnosed with bipolar disorder (BP), major depressive disorder (MDD), or schizophrenia (SCZ) who have full insight and normal intelligence. Eighteen-month menstruation histories were recorded with pictorial blood loss assessment chart assessments of HMB. Multivariate analyses were conducted to obtain odds ratios (ORs) and 95% confidence intervals (CIs). Drug effects on cognition were assessed with the MATRICS Consensus Cognitive Battery (MCCB). HMB prevalence were: BP, 25.85%; MDD, 18.78%; and SCH, 13.7%. High glycosylated hemoglobin (HbA1c) level was a strong risk factor for HMB [BP OR, 19.39 (16.60-23.01); MDD OR, 2.69 (4.59-13.78); and SCZ OR, 9.59 (6.14-12.43)]. Additional risk factors included fasting blood sugar, 2-h postprandial blood glucose, and use of the medication valproate [BP: OR, 16.00 (95%CI 12.74-20.22); MDD: OR, 13.88 (95%CI 11.24-17.03); and SCZ OR, 11.35 (95%CI 8.84-19.20)]. Antipsychotic, antidepressant, and electroconvulsive therapy use were minor risk factors. Pharmacotherapy-induced visual learning impairment was associated with HMB [BP: OR, 9.01 (95%CI 3.15-13.44); MDD: OR, 5.99 (95%CI 3.11-9.00); and SCZ: OR, 7.09 (95%CI 2.99-9.20)]. Lithium emerged as a protective factor against HMB [BP: OR, 0.22 (95%CI 0.14-0.40); MDD: OR, 0.30 (95%CI 0.20-0.62); and SCZ: OR, 0.65 (95%CI 0.33-0.90)]. In SCZ patients, hyperlipidemia and high total cholesterol were HMB-associated factors (ORs, 1.87-2.22). Psychiatrist awareness of HMB risk is concerningly low (12/257, 2.28%). In conclusion, prescription of VPA should be cautioned for women with mental illness, especially BP, and lithium may be protective against HMB.

Metabolic risk factors of cognitive impairment in young women with major psychiatric disorder.

Background: Cognitive performance improves clinical outcomes of patients with major psychiatric disorder (MPD), but is impaired by hyperglycemia. Psychotropic agents often induce metabolism syndrome (MetS). The identification of modifiable metabolic risk factors of cognitive impairment may enable targeted improvements of patient care. Objective: To investigate the relationship between MetS and cognitive impairment in young women with MPD, and to explore risk factors. Methods: We retrospectively studied women of 18-34 years of age receiving psychotropic medications for first-onset schizophrenia (SCH), bipolar disorder (BP), or major depressive disorder (MDD). Data were obtained at four time points: presentation but before psychotropic medication; 4-8 and 8-12 weeks of psychotropic therapy; and enrollment. MATRICS Consensus Cognitive Battery, (MCCB)-based Global Deficit Scores were used to assess cognitive impairment. Multiple logistic analysis was used to calculate risk factors. Multivariate models were used to investigate factors associated with cognitive impairment. Results: We evaluated 2,864 participants. Cognitive impairment was observed in 61.94% of study participants, and was most prevalent among patients with BP (69.38%). HbA1c within the 8-12 week-treatment interval was the most significant risk factor and highest in BP. Factors in SCH included pre-treatment waist circumference and elevated triglycerides during the 8-12 weeks treatment interval. Cumulative dosages of antipsychotics, antidepressants, and valproate were associated with cognitive impairment in all MPD subgroups, although lithium demonstrated a protect effect (all P < 0.001). Conclusions: Cognitive impairment was associated with elevated HbA1c and cumulative medication dosages. Pre-treatment waist circumference and triglyceride level at 8-12 weeks were risk factors in SCH. Monitoring these indices may inform treatment revisions to improve clinical outcomes.

Proposed protocol for the investigation of the safety and efficacy of the COVID-19 vaccine for patients with psychosis, with pilot safety findings from a Chinese psychiatrist's self-experiment.

We present a study protocol designed to test the safety and efficacy of the 2019 coronavirus disease (COVID-19) vaccine in patients with major psychotic disease. A secondary objective is to investigate optional vaccination methods for these patients. In a self-experiment, a Chinese psychiatrist examined the safety and efficacy of the COVID-19 vaccine under clinical use of typical antipsychotic agents and sedatives (olanzapine, duloxetine, and diazepam). For patients with extremely drug-resistant conditions, the safety of the COVID-19 vaccine under electroconvulsive therapy was also investigated. The entire study process was recorded on high-definition video. This clinical study protocol is, to our knowledge, the first of its kind. Our findings will shed new light on the protection of patients with psychotic diseases from COVID-19 infection. The protocol was registered at Chinese clinical trial registry (www.chictr.org.cn, ChiCTR2100051297).

Calcium imaging reveals depressive- and manic-phase-specific brain neural activity patterns in a murine model of bipolar disorder: a pilot study.

Brain pathological features during manic/hypomanic and depressive episodes in the same patients with bipolar disorder (BPD) have not been described precisely. The study aimed to investigate depressive and manic-phase-specific brain neural activity patterns of BPD in the same murine model to provide information guiding investigation of the mechanism of phase switching and tailored prevention and treatment for patients with BPD. In vivo two-photon imaging was used to observe brain activity alterations in the depressive and manic phases in the same murine model of BPD. Two-photon imaging showed significantly reduced Ca2+ activity in temporal cortex pyramidal neurons in the depression phase in mice exposed to chronic unpredictable mild stress (CUMS), but not in the manic phase in mice exposed to CUMS and ketamine. Total integrated calcium values correlated significantly with immobility times. Brain Ca2+ hypoactivity was observed in the depression and manic phases in the same mice exposed to CUMS and ketamine relative to naïve controls. The novel object recognition preference ratio correlated negatively with the immobility time in the depression phase and the total distance traveled in the manic phase. With recognition of its limitations, this study revealed brain neural activity impairment indicating that intrinsic emotional network disturbance is a mechanism of BPD and that brain neural activity is associated with cognitive impairment in the depressive and manic phases of this disorder. These findings are consistent with those from macro-imaging studies of patients with BPD. The observed correlation of brain neural activity with the severity of depressive, but not manic, symptoms need to be investigated further.

A typical antipsychotic treatment induced gradually expanding white matter alterations in healthy individuals with persistent auditory verbal hallucinations-an artificially controlled pilot study.

OBJECTIVE: The aim of this study was to explore the effects of atypical antipsychotics (AaPs) on brain white matter (WM) tracts in healthy individuals with auditory verbal hallucinations (Hi-AVHs). METHODS: We analyzed neuroimaging, AVH symptoms, and cognitive assessment data obtained from 39 Hi-AVHs who reported being distressed by persistent AVHs and volunteered to receive AaP treatment. We used tract-based spatial statistics (TBSS) and t tests to explore AaP pharmacotherapy effects on AVH symptoms and brain WM alterations in Hi-AVH subjects. RESULTS: TBSS and t tests revealed WM alterations after AaP treatment, relative to pretreatment observations. Although AaPs alleviated AVH symptoms, WM alterations in these subjects expanded over 8 months of AaP treatment, encompassing most major WM tracts by the end of the observation period, including the corpus callosum, arcuate fasciculus, cortico-spinal tracts, anterior commissure, and posterior commissure. CONCLUSIONS: The worsening of AaP-associated WM alterations observed in this study suggest that AaPs may not be a good choice for the treatment of Hi-AVHs despite their ability to alleviate AVHs.

Brain Neural Activity Patterns in an Animal Model of Antidepressant-Induced Manic Episodes.

Background: In the treatment of patients with bipolar disorder (BP), antidepressant-induced mania is usually observed. The rate of phase switching (from depressive to manic) in these patients exceeds 22%. The exploration of brain activity patterns during an antidepressant-induced manic phase may aid the development of strategies to reduce the phase-switching rate. The use of a murine model to explore brain activity patterns in depressive and manic phases can help us to understandthe pathological features of BP. The novel object recognition preference ratio is used to assess cognitive ability in such models. Objective: To investigate brain Ca2+ activity and behavioral expression in the depressive and manic phases in the same murine model, to aid understanding of brain activity patterns in phase switching in BP. Methods: In vivo two-photon imaging was used to observe brain activity alterations in a murine model in which induce depressive-like and manic-like behaviors were induced sequentially. The immobility time was used to assess depressive-like symptoms and the total distance traveled was used to assess manic-like symptoms. Results: In vivo two-photon imaging revealed significantly reduced brain Ca2+ activity in temporal cortex pyramidal neurons in the depressive phase in mice exposed to chronic unpredictable mild stress compared with naïve controls. The brain Ca2+ activity correlated negatively with the novel object recognition preference ratio within the immobility time. Significantly increased brain Ca2+ activity was observed in the ketamine-induced manic phase. However, this activity did not correlate with the total distance traveled. The novel object recognition preference ratio correlated negatively with the total distance traveled in the manic phase.

COMT-Val158Met polymorphism modulates antipsychotic effects on auditory verbal hallucinations and temporal lobe gray matter volumes in healthy individuals-symptom relief accompanied by worrisome volume reductions.

Investigation of auditory verbal hallucinations (AVHs) in schizophrenics is complicated by psychiatric symptoms. Investigating healthy individuals with AVHs (H-AVHs) can obviate such confounding factors. The objective of this study was to explore the effects of antipsychotic treatment on AVHs and gray matter volumes (GMVs) in H-AVH subjects and whether such are effects are influenced by COMT-Val158Met genotype. Magnetic resonance imaging (MRI) and genotyping studies were completed for 42 H-AVH subjects and 42 well-matched healthy controls (HCs). COMT-Met/Met homozygotes (158th codon) were identified as COMT-Met genotype; COMT-Met/Val heterozygotes and COMT-Val/Val homozygotes were identified as COMT-Val genotype. Data were compared across groups (H-AVH vs. HC, and between genotypes) with two-sample t-tests. The H-AVH COMT-Met group showed a stronger response to antipsychotic treatment than the H-AVH COMT-Val group (p < 0.001). Both H-AVH genotype groups exhibited temporal lobe GMV reductions after treatment, and relative to their respective genotype-matched HC groups. Antipsychotic treatment effects in H-AVH subjects were influenced by COMT-Val158Met genotype and associated with widespread GMV reductions. These findings provide clues for further exploration of treatment targets for AVHs. Treatment associated GMV reductions, however, raise concerns about use of antipsychotics in H-AVH subjects.

Add-on atypical anti-psychotic treatment alleviates auditory verbal hallucinations in patients with chronic post-traumatic stress disorder.

Auditory verbal hallucinations are common symptoms of post traumatic distress disorder. Previous studies have demonstrated alterations in the salience network (SN) in patients with post traumatic distress disorder and that hyperactivity of the SN is associated with AVHs in patients with psychosis. Patients with post traumatic distress disorder may benefit from aripiprazole; however, studies investigating the effect of aripiprazole on AVHs and activity in the SN in patients with post traumatic distress disorder are scarce. Therefore, we conducted an outcomes analysis using functional magnetic resonance imaging to explore the effects of add-on aripiprazole treatment on AVHs and brain functional connectivity in patients with post traumatic distress disorder. AVHs were alleviated by add-on aripiprazole treatment (Auditory Hallucination Rating Scale [AHRS] score reduced by ≥ 50%) in 22.7% of patients. Functional activity in the SN was obviously decreased in patients in whom AHRS scores were reduced ≥ 50% following add-on aripiprazole treatment compared to patients in whom AHRS scores were reduced by <50%. The decrease in functional connectivity within the SN was significantly correlated with the reduction in total AHRS scores. Although this study was associated with several limitations, the findings suggest that add-on aripiprazole treatment can alleviate AVHs in patients with post traumatic distress disorder by reducing activity in the SN.

The genomics of schizophrenia: Shortcomings and solutions.

Due to recent advances in human genomic technologies, there have been explosive interests and extensive research on the genomics of schizophrenia, a severe psychiatric disorder characterized by social cognitive deficits, hallucinations, and delusions. These new technologies, including next-generation sequencing (NGS), genome-wide association studies (GWAS), and the Clustered Regularly Interspaced Short Palindromic Repeats-associated nuclease 9 (CRISPR/Cas9) genome editing platform are capable of interrogating and editing the genome directly. In the past few years, these efforts have led to the identification of important loci and genes susceptible to schizophrenia. The findings have increased our understanding of the underlying genetic causes of schizophrenia and aided in the development of new approaches for more effectively diagnosing and treating schizophrenia. Despite the substantial progress, there are several unanswered questions about the genomics of schizophrenia, and there are a number of potential shortcomings in the current literature considering the complexity of the disease and limits of the current technologies. In the present review, we assessed the existing literature on the genomics of schizophrenia, identifying the strengths and study design shortcomings from the following aspects: elucidation of the pathogenesis, early risk prediction and diagnosis, and the treatment of schizophrenia. Moreover, we have proposed solutions to overcome the shortcomings of past studies. Lastly, we have discussed the importance of developing multidisciplinary teams and global research groups in order to improve the lives of schizophrenic patients globally.

Aberrant patterns of local and long-range functional connectivity densities in schizophrenia.

Schizophrenia is a disorder of brain dysconnectivity, and both the connection strength and connection number are disrupted in patients with schizophrenia. The functional connectivity density (FCD) can reflect alterations in the connection number. Alterations in the global FCD (gFCD) in schizophrenia were previously demonstrated; however, alterations in two other indices of the pathological characteristics of the brain, local FCD (lFCD) and long-range FCD (lrFCD), have not been revealed. To investigate lFCD and lrFCD alterations in patients with schizophrenia, 95 patients and 93 matched healthy controls were examined using structural and resting-state functional magnetic resonance imaging scanning. lFCD and lrFCD were measured using FCD mapping, and differences were identified using a two-sample t-test in a voxel-wise manner, with age and gender considered to increase variability. Multiple comparisons were performed using a false discovery rate method with a corrected threshold of P<0.05. Our analysis showed that lFCD was primarily decreased in the postcentral gyrus, right calcarine sulcus, and inferior occipital gyrus lobule, but increased in the bilateral subcortical regions. The differences in lFCD were more pronounced and complicated than those in lrFCD. In summary, in contrast with previous studies that focused on the connection strength, our findings, from the perspective of connection number, indicate that schizophrenia is a disorder of brain dysconnectivity, particularly affecting the local functional connectivity network, and support the hypothesis that schizophrenia is associated with a widespread cortical functional connectivity/activity deficit, with hyper- and/or hypo-connectivity/activity coexisting in some cortical or subcortical regions.