Tian-Mei Si

Antipsychotic drug prescription for schizophrenia in East Asia: rationale for change

Abstract  The purpose of this international collaborative study was to investigate the prescription patterns of antipsychotic drugs for schizophrenia in East Asia and to analyze factors that affect these patterns. Prescription patterns for patients admitted for treatment of schizophrenia were surveyed using a standardized protocol from six East‐Asian region/countries: China, Hong Kong, Japan, Korea, Singapore and Taiwan. Patients’ social and clinical characteristics, psychiatric symptoms, course of illness, and adverse effects of medications were systematically assessed and recorded. Prescriptions of the first‐ and second‐generation antipsychotic drugs were compared. A total of 2399 patients were recruited. The second‐generation drugs comprised 28.1% of all prescribed antipsychotics, and 46% of the antipsychotic prescriptions were in the context of polypharmacy. The mean dosage of antipsychotics for the whole sample was 675.3 + 645.1 mg chlorpromazine equivalents. Japan had a high frequency of prescribing high doses and polypharmacy; Singapore had a high utilization of depot injections while China had a higher prescription of clozapine. Using multiple logistic regression analysis, distinctions in the prescription patterns of antipsychotic drugs were found: first‐generation drugs were mainly for controlling aggressive behavior, while second‐generation drugs were targeted at the alleviation of positive, negative psychotic symptoms as well as disruptive behavior in schizophrenia. The present collaborative study highlighted differences in the prescription patterns, especially the under‐utilization of second‐generation antipsychotic drugs in East Asia. The pattern of antipsychotic medication use varied from country to country and is likely to be influenced by the prevailing health‐care system, the availability and cost of the drugs.

Amplitude of low-frequency oscillations in first-episode, treatment-naive patients with major depressive disorder: a resting-state functional MRI study.

Background Resting-state fMRI is a novel approach to measure spontaneous brain activity in patients with major depressive disorder (MDD). Although most resting-state fMRI studies have focused on the examination of temporal correlations between low-frequency oscillations (LFOs), few studies have explored the amplitude of these LFOs in MDD. In this study, we applied the approaches of amplitude of low-frequency fluctuation (ALFF) and fractional ALFF to examine the amplitude of LFOs in MDD. Methodology/Principal Findings A total of 36 subjects, 18 first-episode, treatment-naive patients with MDD matched with 18 healthy controls (HCs) completed the fMRI scans. Compared with HCs, MDD patients showed increased ALFF in the right fusiform gyrus and the right anterior and posterior lobes of the cerebellum but decreased ALFF in the left inferior temporal gyrus, bilateral inferior parietal lobule, and right lingual gyrus. The fALFF in patients was significantly increased in the right precentral gyrus, right inferior temporal gyrus, bilateral fusiform gyrus, and bilateral anterior and posterior lobes of the cerebellum but was decreased in the left dorsolateral prefrontal cortex, bilateral medial orbitofrontal cortex, bilateral middle temporal gyrus, left inferior temporal gyrus, and right inferior parietal lobule. After taking gray matter (GM) volume as a covariate, the results still remained. Conclusions/Significance These findings indicate that MDD patients have altered LFO amplitude in a number of regions distributed over the frontal, temporal, parietal, and occipital cortices and the cerebellum. These aberrant regions may be related to the disturbances of multiple emotion- and cognition-related networks observed in MDD and the apparent heterogeneity in depressive symptom domains. Such brain functional alteration of MDD may contribute to further understanding of MDD-related network imbalances demonstrated in previous fMRI studies.

The effects of antidepressant treatment on resting-state functional brain networks in patients with major depressive disorder

Although most knowledge regarding antidepressant effects is at the receptor level, the neurophysiological correlates of these neurochemical changes remain poorly understood. Such an understanding could benefit from elucidation of antidepressant effects at the level of neural circuits, which would be crucial in identifying biomarkers for monitoring treatment efficacy of antidepressants. In this study, we recruited 20 first‐episode drug‐naive major depressive disorder (MDD) patients and performed resting‐state functional magnetic resonance imaging (MRI) scans before and after 8 weeks of treatment with a selective serotonin reuptake inhibitor—escitalopram. Twenty healthy controls (HCs) were also scanned twice with an 8‐week interval. Whole‐brain connectivity was analyzed using a graph‐theory approach—functional connectivity strength (FCS). The analysis of covariance of FCS was used to determine treatment‐related changes. We observed significant group‐by‐time interaction on FCS in the bilateral dorsomedial prefrontal cortex and bilateral hippocampi. Post hoc analyses revealed that the FCS values in the bilateral dorsomedial prefrontal cortex were significantly higher in the MDD patients compared to HCs at baseline and were significantly reduced after treatment; conversely, the FCS values in the bilateral hippocampi were significantly lower in the patients at baseline and were significantly increased after treatment. Importantly, FCS reduction in the dorsomedial prefrontal cortex was significantly correlated with symptomatic improvement. Together, these findings provided evidence that this commonly used antidepressant can selectively modulate the intrinsic network connectivity associated with the medial prefrontal‐limbic system, thus significantly adding to our understanding of antidepressant effects at a circuit level and suggesting potential imaging‐based biomarkers for treatment evaluation in MDD. Hum Brain Mapp 36:768–778, 2015.

Interhemispheric Functional Connectivity and Its Relationships with Clinical Characteristics in Major Depressive Disorder: A Resting State fMRI Study

Background Abnormalities in large-scale, structural and functional brain connectivity have been increasingly reported in patients with major depressive disorder (MDD). However, MDD-related alterations in functional interaction between the cerebral hemispheres are still not well understood. Resting state fMRI, which reveals spontaneous neural fluctuations in blood oxygen level dependent signals, provides a means to detect interhemispheric functional coherence. We examined the resting state functional connectivity (RSFC) between the two hemispheres and its relationships with clinical characteristics in MDD patients using a recently proposed measurement named “voxel-mirrored homotopic connectivity (VMHC)”. Methodology/Principal Findings We compared the interhemispheric RSFC, computed using the VMHC approach, of seventeen first-episode drug-naive patients with MDD and seventeen healthy controls. Compared to the controls, MDD patients showed significant VMHC decreases in the medial orbitofrontal gyrus, parahippocampal gyrus, fusiform gyrus, and occipital regions including the middle occipital gyrus and cuneus. In MDD patients, a negative correlation was found between VMHC of the fusiform gyrus and illness duration. Moreover, there were several regions whose VMHC showed significant negative correlations with the severity of cognitive disturbance, including the prefrontal regions, such as middle and inferior frontal gyri, and two regions in the cereballar crus. Conclusions/Significance These findings suggest that the functional coordination between homotopic brain regions is impaired in MDD patients, thereby providing new evidence supporting the interhemispheric connectivity deficits of MDD. The significant correlations between the VMHC and clinical characteristics in MDD patients suggest potential clinical implication of VMHC measures for MDD. Interhemispheric RSFC may serve as a useful screening method for evaluating MDD where neural connectivity is implicated in the pathophysiology.

Association study of the human FZD3 locus with schizophrenia

The FZD3 protein is a transmembrane receptor for secreted Wnt glycoproteins involved in the Wnt signal transduction cascades. The alteration of Wnt signal transduction cascades has been thought to be involved in producing the cytoarchitectural defects observed in schizophrenia. Because the human FZD3 gene is mapped to chromosome 8p21, which is a potential region containing a gene for schizophrenia, it may play a role in conferring susceptibility to the disease. This study was conducted with the detection of three single nucleotide polymorphisms (SNPs) located within the FZD3 locus by using the polymerase chain reaction-based restriction fragment length polymorphism (RFLP) analysis among 246 schizophrenic family trios of Chinese Han descent.The transmission disequilibrium test (TDT) demonstrated that the three SNPs all showed a preferential transmission with a p value ranging from.0003-.000007. The global chi-squared test for haplotype transmission also showed a strong association (chi(2) = 48.84, df = 7, p <.000001).The strong association between the FZD3 locus and schizophrenia suggests that the gene itself may play a role in underlying schizophrenia, although a nearby gene responsible for predisposing to the illness cannot be ruled out.

Short-term effects of escitalopram on regional brain function in first-episode drug-naive patients with major depressive disorder assessed by resting-state functional magnetic resonance imaging.

BACKGROUND Most knowledge regarding the effects of antidepressant drugs is at the receptor level, distal from the nervous system effects that mediate their clinical efficacy. Using functional magnetic resonance imaging (fMRI), this study investigated the effects of escitalopram, a selective serotonin reuptake inhibitor (SSRI), on resting-state brain function in patients with major depressive disorder (MDD). METHOD Fourteen first-episode drug-naive MDD patients completed two fMRI scans before and after 8 weeks of escitalopram therapy. Scans were also acquired in 14 matched healthy subjects. Data were analyzed using the regional homogeneity (ReHo) approach. RESULTS Compared to controls, MDD patients before treatment demonstrated decreased ReHo in the frontal (right superior frontal gyrus), temporal (left middle and right inferior temporal gyri), parietal (right precuneus) and occipital (left superior occipital gyrus and right cuneus) cortices, and increased ReHo in the left dorsal medial prefrontal gyrus and left anterior lobe of the cerebellum. Compared to the unmedicated state, ReHo in the patients after treatment was decreased in the left dorsal medial prefrontal gyrus, the right insula and the bilateral thalamus, and increased in the right superior frontal gyrus. Compared to controls, patients after treatment displayed a ReHo decrease in the right precuneus and a ReHo increase in the left anterior lobe of the cerebellum. CONCLUSIONS Successful treatment with escitalopram may be associated with modulation of resting-state brain activity in regions within the fronto-limbic circuit. This study provides new insight into the effects of antidepressants on functional brain systems in MDD.

Positive association of the human frizzled 3 (FZD3) gene haplotype with schizophrenia in Chinese Han population

Frizzled 3 (FZD3) gene is located on chromosome 8p21, a region that has been implicated in schizophrenia in genetic linkage studies. The FZD3 is a transmembrane receptor required for Wnt signal transduction cascades that have been thought to be involved in producing the cytoarchitectural defects observed in schizophrenia. Previous work has showed a strong association between FZD3 locus and schizophrenia in family‐based study. To confirm this issue further, we investigated a genetic association between four single nucleotide polymorphisms (SNPs) located in the FZD3 gene and schizophrenia by case‐control study using polymerase chain reaction (PCR)‐based restriction fragment length polymorphism (RFLP) in the Chinese Han population. Our studies showed the SNPs rs2323019 and rs880481 have significant differences in both genotype and allele frequencies between control subjects and schizophrenic patients (rs2323019: Allele A > G, χ2 = 6.7277, df = 1, P = 0.0095; Genotype, χ2 = 10.6583, df = 2, P = 0.0049; rs880481: Allele A > G, χ2 = 10.3945, df = 1, P = 0.0013; Genotype, χ2 = 16.8049, df = 2, P = 0.0002). In addition, we constructed three‐locus haplotypes to test their association with schizophrenia. The globe chi‐squared test for haplotype analysis showed a significant association (χ2 = 66.38, df = 7, P < 0.000001). These results suggested that the FZD3 gene might be involved in the predisposition to schizophrenia.

Chronic antipsychotic drug administration alters the expression of neuregulin 1β, ErbB2, ErbB3, and ErbB4 in the rat prefrontal cortex and hippocampus

Neuregulin 1 (NRG1) has been identified as a susceptibility gene for schizophrenia, and dysregulation of NRG1 and its ErbB receptors is implicated in the pathophysiology of the disorder. The present study examined the protein expression levels of NRG1beta, ErbB2, ErbB3 and ErbB4 in the rat prefrontal cortex and hippocampus following a 4-wk administration of haloperidol (1 mg/kg i.p.), clozapine (10 mg/kg i.p.), or risperidone (1 mg/kg i.p.) by using immunohistochemistry and Western blot. The results showed that haloperidol promoted the expression of NRG1beta and ErbB4, whereas clozapine inhibited NRG1beta expression in the rat prefrontal cortex. Both haloperidol and clozapine significantly increased the protein levels of NRG1beta and ErbB receptors in the rat hippocampus. Repeated administration of risperidone only increased the expression of NRG1beta and ErbB4 in the hippocampus. Our findings demonstrate that antipsychotic drugs differentially regulate the expression of NRG1 and ErbB receptors in the rat brain, which may provide insight into the molecular basis of the pharmacological profile of antipsychotic drugs.

The Level of Serum Brain-Derived Neurotrophic Factor Is Associated With the Therapeutic Efficacy of Modified Electroconvulsive Therapy in Chinese Patients With Depression

Objective: To investigate the association between the level of serum brain-derived neurotrophic factor (sBDNF) and the therapeutic efficacy of modified electroconvulsive therapy (MECT) in Chinese patients with depressive disorder. Methods: Twenty-eight patients with depressive episode and 28 healthy subjects were recruited in the current study. The sBDNF level was examined in all subjects before treatment and after a 2-week treatment with MECT in patients with depression. The severity of depression was measured according to the 17-item Hamilton Rating Scale for Depression in patients with depression. Results: The severity of depression reduced significantly in patients with depression after a 2-week treatment with MECT (31.39 [SD, 4.65] vs 8.14 [5.52], P < 0.001). Serum BDNF level in patients with depression was significantly lower than that of the control group before treatment (5.66 [SD, 2.07] vs 9.17 [SD, 1.26] ng/mL, P < 0.001), then increased remarkably to the level of control subjects 2 weeks after MECT (7.90 [SD, 3.42] ng/mL). The increasing rate of sBDNF in patients with depression was significantly correlated with the decreasing rate of the total 17-item Hamilton Rating Scale for Depression score (r = 0.532, P = 0.004) and cluster scores of cognitive dysfunction (P = 0.018) and retardation (P = 0.048). Conclusion: The change in sBDNF is associated with the therapeutic efficacy of MECT in Chinese patients with depression.

Blockade of corticotropin‐releasing hormone receptor 1 attenuates early‐life stress‐induced synaptic abnormalities in the neonatal hippocampus

Adult individuals with early stressful experience exhibit impaired hippocampal neuronal morphology, synaptic plasticity and cognitive performance. While our knowledge on the persistent effects of early‐life stress on hippocampal structure and function and the underlying mechanisms has advanced over the recent years, the molecular basis of the immediate postnatal stress effects on hippocampal development remains to be investigated. Here, we reported that repeated blockade of corticotropin‐releasing hormone receptor 1 (CRHR1) ameliorated postnatal stress‐induced hippocampal synaptic abnormalities in neonatal mice. Following the stress exposure, pups with fragmented maternal care showed retarded dendritic outgrowth and spine formation in CA3 pyramidal neurons and reduced hippocampal levels of synapse‐related proteins. During the stress exposure, repeated blockade of glucocorticoid receptors (GRs) by daily administration of RU486 (100 µg g−1) failed to attenuate postnatal stress‐evoked synaptic impairments. Conversely, daily administration of the CRHR1 antagonist antalarmin hydrochloride (20 µg g−1) in stressed pups normalized hippocampal protein levels of synaptophysin, postsynaptic density‐95, nectin‐1, and nectin‐3, but not the N‐methyl‐d‐aspartate receptor subunits NR1 and NR2A. Additionally, GR or CRHR1 antagonism attenuated postnatal stress‐induced endocrine alterations but not body growth retardation. Our data indicate that the CRH‐CRHR1 system modulates the deleterious effects of early‐life stress on dendritic development, spinogenesis, and synapse formation, and that early interventions of this system may prevent stress‐induced hippocampal maldevelopment.