Few studies have reported on brain functional differences between healthy individuals with auditory verbal hallucinations (Hi-AVH) with and without insight, so we designed a study to address this ...knowledge gap. We enrolled 12 Hi-AVH with insight, 15 Hi-AVH without insight, and 15 AVH-free controls (Healthy controls). Global functional connectivity density (gFCD) mapping was used to estimate brain networks. We found that the most common alterations in both Hi-AVH groups were increased gFCD in superior parietal lobule and superior temporal gyrus. We also found that distinct brain functional patterns of Hi-AVH without insight comprised lower gFCD in the frontal lobe oculomotor area, dorsolateral prefrontal cortex, supramarginal gyrus, primary auditory cortex, sensorimotor cortex, ventral anterior, and posterior cingulate Our pilot findings support the hypothesis that abnormal reciprocal action in the circuits for processing perception, memory, language, and attentional control may be pathological features of auditory verbal hallucinations.
Abstract
Schizophrenia is a severe mental illness, as the efficacies of current antipsychotic medications are far from satisfactory. An improved understanding of the signaling molecules involved in ...schizophrenia may provide novel therapeutic targets. Acid sphingomyelinase (ASM) catalyzes cellular membrane sphingomyelin into ceramide, which is further metabolized into sphingosine-1-phophate (S1P). ASM, ceramide, and S1P at the cell surface exert critical roles in the regulation of biophysical processes that include proliferation, apoptosis, and inflammation, and are thereby considered important signaling molecules. Although research on the ASM/ceramide system is still in its infancy, structural and metabolic abnormalities have been demonstrated in schizophrenia. ASM/ceramide system dysfunction is linked to the two important models of schizophrenia, the dopamine (DA) hypothesis through affecting presynaptic DA signaling, and the vulnerability-stress-inflammation model that includes the contribution of stress on the basis of genetic predisposition. In this review, we highlight the current knowledge of ASM/ceramide system dysfunction in schizophrenia gained from human and animal studies, and formulate future directions from the biological landscape for the development of new treatments. Collectively, these discoveries suggest that aberrations in the ASM/ceramide system, especially in ASM activity and levels of ceramide and S1P, may alter cerebral microdomain structure and neuronal metabolism, leading to neurotransmitter (e.g., DA) dysfunction and neuroinflammation. As such, the ASM/ceramide system may offer therapeutic targets for novel medical interventions. Normalization of the aberrant ASM/ceramide system or ceramide reduction by using approved functional inhibitors of ASM, such as fluvoxamine and rosuvastatin, may improve clinical outcomes of patients with schizophrenia. These transformative findings of the ASM/ceramide system in schizophrenia, although intriguing and exciting, may pose scientific questions and challenges that will require further studies for their resolution.
Few advances in schizophrenia research have been translated into clinical practice, despite 60 years of serum biomarkers studies and 50 years of genetic studies. During the last 30 years, ...neuroimaging studies on schizophrenia have gradually increased, partly due to the beautiful prospect that the pathophysiology of schizophrenia could be explained entirely by the Human Connectome Project (HCP). However, the fallacy of reverse inference has been a critical problem of the HCP. For this reason, there is a dire need for new strategies or research “bridges” to further schizophrenia at the biological level. To understand the importance of research “bridges,” it is vital to examine the strengths and weaknesses of the recent literature. Hence, in this review, our team has summarized the recent literature (1995–2018) about magnetic resonance imaging (MRI) of schizophrenia in terms of regional and global structural and functional alterations. We have also provided a new proposal that may supplement the HCP for studying schizophrenia. As postulated, despite the vast number of MRI studies in schizophrenia, the lack of homogeneity between the studies, along with the relatedness of schizophrenia with other neurological disorders, has hindered the study of schizophrenia. In addition, the reverse inference cannot be used to diagnose schizophrenia, further limiting the clinical impact of findings from medical imaging studies. We believe that multidisciplinary technologies may be used to develop research “bridges” to further investigate schizophrenia at the single neuron or neuron cluster levels. We have postulated about future strategies for overcoming the current limitations and establishing the research “bridges,” with an emphasis on multimodality imaging, molecular imaging, neuron cluster signals, single transmitter biomarkers, and nanotechnology. These research “bridges” may help solve the reverse inference fallacy and improve our understanding of schizophrenia for future studies.
Despite decades of research and major efforts, malignant brain tumors remain among the deadliest of all cancers. Recently, an increasing number of psychiatric drugs has been proven to possess ...suppressing activities against brain tumors, and rapid progress has been made in understanding the potential mechanisms of action of these drugs. In particular, the traditional mood stabilizer valproic acid, the widely used antidepressants fluoxetine and escitalopram oxalate, and the atypical psychiatric drug aripiprazole have demonstrated promise for application in brain tumor treatment strategies through multiple lines of laboratory, preclinical, and clinical evidence. The unexpected discovery of the anticancer properties of these drugs has ignited interest in the repurposing of other psychiatric drugs to combat brain cancer. In this review, we synthesize recent progress in understanding the potential molecular mechanisms underlying the brain cancer–killing activities of representative psychiatric drugs. We also identify key limitations in the repurposing of these medications that must be overcome to enhance our ability to successfully prevent and treat brain cancer, especially in the most vulnerable groups of patients, such as children and adolescents, pregnant women, and those with unfavorable genetic variants. Moreover, we propose perspectives that may guide future research and provide long-awaited new hope to patients with brain cancer and their families.
Cardio-renal profiles are available from cardiovascular outcome trials of glucagon-like peptide-1 receptor agonists (GLP-1 RAs).
A comprehensive systematic review of Embase, Medline, Web of ...Knowledge, and CENTRAL databases was conducted. Randomized controlled cardiovascular outcome trials of type 2 diabetes mellitus (T2DM) patients administered GLP-1 RAs were included. The following primary outcomes were examined: cardiovascular death, major adverse cardiovascular events (MACE), myocardial infarction, stroke, mortality, heart failure, hypoglycemia, pancreatitis, and thyroid carcinoma. Secondary outcomes included: composite kidney outcome, worsening kidney function, macroalbuminuria, and retinopathy.
Seven trials involving 56,004 patients and eight interventions were identified. Albiglutide was associated with fewer MACE and myocardial infarction events compared with lixisenatide. Lixisenatide was related to a greater number of stroke events and cardiovascular deaths compared to once-weekly semaglutide and oral semaglutide, respectively. Improved mortality was associated with oral semaglutide compared with once-weekly semaglutide, albiglutide, dulaglutide, exenatide, or lixisenatide. Risks of heart failure, thyroid carcinoma, and pancreatitis were similar among all the treatments. Weighting of the nine primary outcomes identified oral semaglutide as first among the eight treatments examined. Among three of the secondary outcomes, once-weekly semaglutide ranked first. Better composite kidney outcome was observed with once-weekly semaglutide than with dulaglutide or exenatide; once-weekly semaglutide improved macroalbuminuria compared with exenatide or lixisenatide; and albiglutide, exenatide, and placebo was associated with fewer cases of retinopathy compared with once-weekly semaglutide. Meanwhile, kidney function was less likely to worsen with dulaglutide than with lixisenatide or placebo.
Semaglutide should be considered when GLP-1 RAs are indicated for T2DM patients.
Introduction
While the psychiatric benefits of ketamine have been verified through clinical trials, there is limited information about ketamine augmentation in patients with treatment‐resistant ...bipolar depression (TRBPD). Hence, in the present study, we investigate the therapeutic efficacy and functional brain alterations associated with multi‐infusion ketamine augmentation in patients with TRBPD.
Methods
The present three‐week study included 38 patients with TRBPD, all of whom received a series of nine ketamine injections over the study period. The Hamilton Depression Rating Scale (HAMD) was used to assess the effects of multi‐infusion ketamine combined with mood stabilizers. Brain function was evaluated by global functional connectivity density (gFCD).
Results
Adjunctive treatment with multiple infusions of ketamine, when combined with a mood stabilizer, could effectively alleviate depressive symptoms for one week, yet the symptoms began to relapse during the second week. Functional brain alterations were detected via gFCD. Specifically, gFCD reductions were mainly found in the bilateral insula, right caudate nucleus, and bilateral inferior frontal gyrus, while increased gFCD was mainly located in the bilateral postcentral gyrus, subgenual anterior cingulate cortex, bilateral thalamus, and cerebellum. Although gFCD alterations were sustained for up to three weeks after the first ketamine infusion, the antidepressant effects of ketamine augmentation sharply declined from the end of the second week of treatment.
Conclusions
Multi‐infusion ketamine augmentation can rapidly alleviate depressive symptoms in patients with TRBPD. The clinical effects were primarily visible in the first week after treatment and partially sustained for two weeks; however, the therapeutic effects and related functional brain alterations sharply decreased from the end of the second week. Based on these findings, we demonstrated that the clinical efficacy and functional brain alterations induced by ketamine augmentation are transient.
Comorbid depressive disorders confound the diagnosis and therapy of schizophrenia. Using a murine model incorporating both MK801 and chronic unpredictable mild stress exposures, we successfully ...replicated both psychosis and depression. Ex vivo patch clamp recordings and in vivo calcium imaging demonstrated impaired neural activity in the prefrontal cortex (PFC). We then administered triple-drug combinations consisting of two antidepressants (mirtazapine and venlafaxine) plus an antipsychotic (either clozapine or olanzapine), and found improved PFC neuronal activity and performance in behavioral assays. Moreover, the addition of metformin to both psychotropic drug combinations brought further improvements in depressive and schizophrenic-like behaviors and physiological parameters. In summary, our data modeled the neuropathophysiology of schizophrenia with comorbid depression, and may inform drug intervention strategies.
Schizophrenia is frequently accompanied by depressive symptoms, but the pathological mechanisms remain to be elucidated. In this study, we used chronic unpredicted mild stress plus MK801 injection to ...generate a mouse model of schizophrenia with depression, in which
2-photon calcium imaging and electrophysiological recordings were performed in conjunction with behavioral phenotyping. Compared to mice models with classical depression or to schizophrenia models, the animal models with schizophrenia and depression comorbidity presented worse psychotic and depressive symptoms. These behavioral deficits are associated with impaired neuronal calcium activities in the frontal cortex and thalamic nuclei. Moreover, in sharp contrast to classical models that have a satisfactory response to antipsychotic or antidepressant drugs, this novel schizophrenia with depression model is resilient to combined drug treatment in terms of behavioral and functional recovery. Taken together, these data indicate that schizophrenia with depression likely involves a unique pathophysiology that is different from schizophrenia or depression alone.
Objective
This study was performed to investigate the effects and associated global functional connectivity density (gFCD) alterations associated with the use of atypical antipsychotics in healthy ...individuals with auditory verbal hallucinations (Hi-AVHs) using gFCD mapping techniques.
Methods
A magnetic resonance imaging database of 38 Hi-AVHs with chronic or severe AVH symptoms was generated. The Hi-AVHs were administered an atypical antipsychotic (risperidone) for 24 weeks and monitored for a treatment response. All patients underwent functional magnetic resonance imaging pre- and post-treatment.
Results
gFCD alterations were found in the auditory-memory-language and visual circuit regions pre- and post-treatment. However, gFCD alterations differed between patients with strong and weak treatment responses.
Conclusion
This is the first report to show that atypical antipsychotics can improve the symptoms of AVHs and that the treatment effects are associated with gFCD alterations in the auditory-memory-language circuit. These findings provide a foundation for future exploration of new treatment strategies for Hi-AVHs.
IMPORTANCE: Patients with schizophrenia are considered to have many risk factors for the development of cancer. However, the incidence of breast cancer in women with schizophrenia compared with the ...general population remains uncertain. OBJECTIVE: To perform an updated meta-analysis to evaluate the association between schizophrenia and the risk of breast cancer. DATA SOURCES: A systematic search of the PubMed and EMBASE databases was conducted using the search terms schizophrenia, schizophrenic, psychosis, combined with breast and cancer, tumor, neoplasm, or carcinoma. The final literature search was performed on August 15, 2017. STUDY SELECTION: Cohort studies reporting the standardized incidence ratio (SIR) for the risk of breast cancer in women with schizophrenia compared with the general population. DATA EXTRACTION AND SYNTHESIS: The meta-analysis adhered to Meta-analysis of Observational Studies in Epidemiology and the Cochrane Handbook for Systematic Reviews of Interventions. Data extraction was performed independently. A random-effects model was used to pool the results, and a recently proposed prediction interval was calculated to describe the heterogeneity. MAIN OUTCOMES AND MEASURES: The SIR for the risk of breast cancer in women with schizophrenia compared with the general population or those without schizophrenia. RESULTS: Twelve cohorts including 125 760 women were included in this meta-analysis. The results of the meta-analysis showed that schizophrenia was associated with a significantly increased risk of breast cancer incidence in women (SIR, 1.31; 95% CI, 1.14-1.50; P < .001), with significant heterogeneity (P < .001; I2 = 89%). Substantial between-study variance was also suggested by the wide prediction interval (0.81-2.10), which indicated that it is possible that a future study will show a decreased breast cancer risk in women with schizophrenia compared with the general population. The subgroup analysis results showed that the association was not significantly affected by whether breast cancer cases were excluded at baseline or the sample size of the included studies. CONCLUSIONS AND RELEVANCE: The incidence of breast cancer in women with schizophrenia is higher than that of the general female population. However, significant heterogeneity exists among the included studies. Women with schizophrenia deserve intensive prevention and treatment of breast cancer.
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