Publications by authors named "Tzu-Yun Wang"

73 Publications

Mechanistic insights into the efficacy of memantine in treating certain drug addictions.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Dec 27;111:110409. Epub 2021 Jul 27.

Neuroimaging Research Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA; Department of Psychiatry and Psychology, Mayo Clinic, 5777 E Mayo Blvd, Phoenix, AZ, USA. Electronic address:

The deleterious effects of the drug addiction epidemic are compounded by treatment strategies that are only marginally efficacious. Memantine is a unique glutamatergic medication with proven ability to attenuate drug addiction in preclinical models. However, clinical translational studies are inconsistent. In this review, we summarize preclinical evidences and clinical trials that investigated the efficacy of memantine in treating patients with alcohol, opiate, cocaine, and nicotine use disorders and discuss the results from a mechanistic point of view. Memantine has shown efficacy in reducing alcohol and opiate craving, consumption, and withdrawal severity. However, in cocaine and nicotine use disorders, memantine did not have significant effect on cravings or consumption. Additionally, memantine was associated with increased subjective effects of alcohol, cocaine, and nicotine. We discuss possible mechanisms behind this variability. Since memantine transiently blocks NMDA receptors and protects neurons from overstimulation by excessive synaptic glutamate, its efficacy should be observed in drug phases that cause hyperglutamatergic states, while hypoglutamatergic drug use states would not resolve with blocking NMDA receptors. Second, memantine pharmacokinetic studies have been done in rodents and healthy volunteers, but not in patients with substance use disorder. Memantine, opiates, cocaine, and nicotine share the same transporter family at the blood brain barrier. This shared transport mechanism could impact brain concentrations of memantine and its effects. In conclusion, memantine remains an intriguing compound in our pharmacopeia with controversial results in treating certain aspects of drug addiction. Further studies are needed to understand the clinical and biological correlates of its efficacy.
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http://dx.doi.org/10.1016/j.pnpbp.2021.110409DOI Listing
December 2021

Corrigendum to "More inflammation but less brain-derived neurotrophic factor in antisocial personality disorder" [Psychoneuroendocrinology (2017; 85, 42-48).

Psychoneuroendocrinology 2021 Sep 7;131:105233. Epub 2021 Jul 7.

Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Addiction Research Center, National Cheng Kung University, Tainan, Taiwan; Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan. Electronic address:

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http://dx.doi.org/10.1016/j.psyneuen.2021.105233DOI Listing
September 2021

HSP70-4 and farnesylated AtJ3 constitute a specific HSP70/HSP40-based chaperone machinery essential for prolonged heat stress tolerance in Arabidopsis.

J Plant Physiol 2021 Jun 29;261:153430. Epub 2021 Apr 29.

Department of Life Sciences, National Central University, 300 Jhong-Da Road, Jhong-Li District, Taoyuan City 32001, Taiwan. Electronic address:

AtJ3 (J3)-a member of the Arabidopsis cytosolic HSP40 family-harbors a C-terminal CaaX motif for farnesylation, which is exclusively catalyzed by protein farnesyltransferase (PFT). Previously, prolonged incubation at 37 °C for 4 d was found to be lethal to the heat-intolerant 5 (hit5) mutant lacking PFT and transgenic j3 plants expressing a CaaX-abolishing J3 construct, indicating that farnesylated J3 is essential for heat tolerance in plants. Given the role of HSP40s as cochaperones of HSP70s, the thermal sensitivity of five individual cytosolic HSP70 (HSP70-1 to HSP70-5) knockout mutants was tested in this study. Only hsp70-4 was sensitive to the prolonged heat treatment like hit5 and j3. The bimolecular fluorescence complementation (BiFC) assay revealed that HSP70-4 interacted with J3 and J3in vivo at normal (23 °C) and high (37 °C) temperatures. At 23 °C, both HSP70-4-J3 and HSP70-4-J3 BiFC signals were uniformly distributed across the cell. However, following treatment at 37 °C, HSP70-4-J3, but not HSP70-4-J3, BiFC signals were detected as discernable foci. These heat-induced HSP70-4-J3 BiFC foci were localized in heat stress granules (HSGs). In addition, hsp70-4 and J3 accumulated more insoluble proteins than the wild type. Thus, farnesylated J3 dictates the chaperone function of HSP70-4 in HSGs. Collectively, this study identified the first HSP70/HSP40-type chaperone machinery playing a crucial role in protecting plants against prolonged heat stress, and demonstrated the significance of protein farnesylation in its protective function.
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http://dx.doi.org/10.1016/j.jplph.2021.153430DOI Listing
June 2021

Identification of potential plasma protein biomarkers for bipolar II disorder: a preliminary/exploratory study.

Sci Rep 2021 05 4;11(1):9452. Epub 2021 May 4.

Department of Research, Taipei Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, New Taipei, 23142, Taiwan.

The diagnostic peripheral biomarkers are still lacking for the bipolar II disorder (BD-II). We used isobaric tags for relative and absolute quantification technology to identify five upregulated candidate proteins [matrix metallopeptidase 9 (MMP9), phenylalanyl-tRNA synthetase subunit beta (FARSB), peroxiredoxin 2 (PRDX2), carbonic anhydrase 1 (CA-1), and proprotein convertase subtilisin/kexin type 9 (PCSK9)] for the diagnosis of BD-II. We analysed the differences in the plasma levels of these candidate proteins between BD-II patients and controls (BD-II, n = 185; Controls, n = 186) using ELISA. To establish a diagnostic model for the prediction of BD-II, the participants were divided randomly into a training group (BD-II, n = 149; Controls, n = 150) and a testing group (BD-II, n = 36; Controls, n = 36). Significant increases were found in all five protein levels between BD-II and controls in the training group. Logistic regression was analysed to form the composite probability score of the five proteins in the training group. Receiver-operating characteristic curve analysis revealed the diagnostic validity of the probability score [area under curve (AUC) = 0.89, P < 0.001]. The composite probability score of the testing group also showed good diagnostic validity (AUC = 0.86, P < 0.001). We propose that plasma levels of PRDX2, CA-1, FARSB, MMP9, and PCSK9 may be associated with BD-II as potential biomarkers.
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http://dx.doi.org/10.1038/s41598-021-88450-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097016PMC
May 2021

Transcranial direct current stimulation (tDCS) may reduce the expired CO concentration among opioid users who smoke cigarettes: a randomized sham-controlled study.

Psychiatry Res 2021 05 15;299:113874. Epub 2021 Mar 15.

Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Psychiatry, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan. Electronic address:

Transcranial direct current stimulation (tDCS) could be a potential treatment for nicotine dependency. Little is known with regards to the efficacy of this treatment in cigarette-smoking patients with heroin dependency. In this sham-controlled study, we probed the effect of 5-day, 20-min, 2-mA-intensity tDCS treatment on the outcomes of cigarette-smoking. Our objectives are to examine the effects of tDCS on two outcomes: objective expired CO concentration and subjective self-reported number of cigarettes smoked per day. A total of 30 patients were randomized into active or sham control groups. The stimulation site was randomized to anodal stimulation of the left dorsal lateral prefrontal cortex or the orbital frontal cortex. The expired CO concentration was recorded. The patients also reported their cigarette consumption and level of craving prior to each 5-day treatment period and after 5 days of follow-up. tDCS was found to be effective in terms of reducing the expired CO concentration, and both groups demonstrated reduced numbers of cigarettes smoked. However, no significant group difference was found with regards to craving tendency. tDCS may affect objective outcomes related to cigarette-smoking among patients with heroin dependence.
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http://dx.doi.org/10.1016/j.psychres.2021.113874DOI Listing
May 2021

Impairment in Emotional Intelligence May Be Mood-Dependent in Bipolar I and Bipolar II Disorders.

Front Psychiatry 2021 18;12:597461. Epub 2021 Feb 18.

Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan.

An emotional intelligence (EI) deficit has been noticed in euthymic bipolar spectrum disorder (BD) patients. However, whether this deficit is affected by mood or subtype is unclear. The aim of this study was to investigate whether an EI deficit is mood-dependent, and which mood symptoms have more impact on EI in BD. Two hundred and thirty participants aged between 18 and 65 years old were recruited [130 BD patients (51 bipolar I disorder (BDI) and 79 bipolar II disorder (BDII): 39.2% males; 91 healthy controls (HCs): 48.4% males)]. The Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT), which contains experiential and strategic EI ratings, was used to assess social cognition. The Hamilton Depression Rating Scale (HDRS) and the Young's Mania Rating Scale (YMRS) were used for evaluating the severity [HAMD and YMRS scores ≦7 were euthymic (BD) and HAMD YMRS sores ≧8 were episodic (BD)]. Analyses of covariance (ANCOVA) were performed, with adjustment for background information between the BD patients and HCs. The results showed that, compared to the HCs, the BD patients showed no difference in any MSCEIT measures, while the BD patients showed lower scores in all MSCEIT measures, except for perceiving emotions. In addition, a main effect of mood state instead of BD subtype was found for the managing emotions branch ( < 0.0007). Regression analyses showed that the duration of illness and HDRS scores were correlated with the scores in the strategic area of the MSCEIT, while age and YMRS scores were more relevant to the scores in the experiential area of the MSCEIT. The results confirm that an EI deficit is mood-dependent in BD patients. In addition, a depressive mood is more related to the strategic EI area, while a manic mood is correlated with the experiential EI area. Understanding the different domains of EI deficits in BD patients may be helpful for developing interventions for BD.
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http://dx.doi.org/10.3389/fpsyt.2021.597461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931827PMC
February 2021

Peripheral BDNF correlated with miRNA in BD-II patients.

J Psychiatr Res 2021 04 13;136:184-189. Epub 2021 Feb 13.

Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan. Electronic address:

Objectives: We have identified the association between peripheral levels of candidate miRNAs (miR-7-5p, miR-142-3p, miR-221-5p, and miR-370-3p) for BD-II in previous study. Most of these miRNAs are associated with regulation of expression of peripheral brain derived neurotrophic factor (BDNF) levels. In order to clarify the underlying mechanism of BDNF and miRNAs in the pathogenesis of BD-II, it is of interest to investigate the relation between the peripheral levels of miR-7-5p, miR-142-3p, miR-221-5p, miR-370-3p with BDNF levels. Because the BDNF Val66Met polymorphism influence the secretion of BDNF, we further stratified the above correlations by this polymorphism.

Methods: We have recruited 98 BD-II patients. Beside analyzing peripheral levels of miR-7-5p, miR-142-3p, miR-221-5p, miR-370-3p, and BDNF, the genetic distribution of the BDNF Val66Met polymorphism was also analyzed.

Results: We found that the miR7-5p, miR221-5p, and miR370-3p significantly correlated with the BDNF levels for all patients. If stratified by the BDNF Val66Met polymorphism, the significant correlation between miR221-5p and miR370-3p with BDNF only remained in the Val/Met genotype. However, the correlation between miR7-5p and BDNF level is significant in all 3 genotypes.

Conclusion: Our result supported that these miRNAs may be involved in the pathomechanism of BD-II through relation with BDNF.
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http://dx.doi.org/10.1016/j.jpsychires.2021.02.018DOI Listing
April 2021

Correction to: Genomic Action of Sigma-1 Receptor Chaperone Relates to Neuropathic Pain.

Mol Neurobiol 2021 Jun;58(6):2542

Cellular Pathobiology Section, Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, NIH/DHHS, Suite 3512, 333 Cassell Drive, Baltimore, MD, 21224, USA.

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http://dx.doi.org/10.1007/s12035-021-02310-3DOI Listing
June 2021

Genomic Action of Sigma-1 Receptor Chaperone Relates to Neuropathic Pain.

Mol Neurobiol 2021 Jun 18;58(6):2523-2541. Epub 2021 Jan 18.

Cellular Pathobiology Section, Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, NIH/DHHS, Suite 3512, 333 Cassell Drive, Baltimore, MD, 21224, USA.

Sigma-1 receptors (Sig-1Rs) are endoplasmic reticulum (ER) chaperones implicated in neuropathic pain. Here we examine if the Sig-1R may relate to neuropathic pain at the level of dorsal root ganglia (DRG). We focus on the neuronal excitability of DRG in a "spare nerve injury" (SNI) model of neuropathic pain in rats and find that Sig-1Rs likely contribute to the genesis of DRG neuronal excitability by decreasing the protein level of voltage-gated Cav2.2 as a translational inhibitor of mRNA. Specifically, during SNI, Sig-1Rs translocate from ER to the nuclear envelope via a trafficking protein Sec61β. At the nucleus, the Sig-1R interacts with cFos and binds to the promoter of 4E-BP1, leading to an upregulation of 4E-BP1 that binds and prevents eIF4E from initiating the mRNA translation for Cav2.2. Interestingly, in Sig-1R knockout HEK cells, Cav2.2 is upregulated. In accordance with those findings, we find that intra-DRG injection of Sig-1R agonist (+)pentazocine increases frequency of action potentials via regulation of voltage-gated Ca2+ channels. Conversely, intra-DRG injection of Sig-1R antagonist BD1047 attenuates neuropathic pain. Hence, we discover that the Sig-1R chaperone causes neuropathic pain indirectly as a translational inhibitor.
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http://dx.doi.org/10.1007/s12035-020-02276-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128747PMC
June 2021

Add-on repetitive transcranial magnetic stimulation in patients with opioid use disorder undergoing methadone maintenance therapy.

Am J Drug Alcohol Abuse 2021 05 10;47(3):330-343. Epub 2021 Jan 10.

Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

: Repetitive transcranial magnetic stimulation (rTMS) shows potential therapeutic effects for individuals with addiction, but few studies have examined individuals with opioid use disorder (OUD).: We conducted an add-on double-blinded, sham-controlled rTMS feasibility pilot trial to examine OUD participants undergoing methadone maintenance therapy (MMT). The current report focused on the effects of rTMS on (1) craving and heroin use behavior and (2) depression, impulsivity, and attention.: Active or sham rTMS treatment was applied to the left dorsolateral prefrontal cortex (DLPFC) over a total of 11 sessions in 4 weeks (15-Hz frequency, 4 seconds per train, intertrain interval of 26 seconds, 40 trains per session) in OUD participants (ClinicalTrials.gov registration number: NCT03229642). Craving, heroin use severity, urine morphine tests, the Hamilton Depression Rating Scale (HDRS), the Barratt Impulsiveness Scale-11 (BIS-11), and the Continuous Performance Tests (CPTs) were measured.: Twenty-two OUD participants were enrolled, of which eleven (8 males) were undergoing active rTMS and nine (8 males) were in the sham rTMS group. After 12 weeks of follow-up, the active rTMS group did not show significantly greater improvements than the sham group with respect to craving, heroin use, or urine morphine test results. However, HDRS scores, BIS-11 attentional subscales, and CPTs commission T-scores (C-TS) were significantly lower in the active rTMS group ( = .003, 0.04, and 0.02, respectively) than in the sham group.: Add-on rTMS did not appear to improve heroin use behavior but may have benefitted depressive symptoms, impulse control and attention in OUD participants undergoing MMT.
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http://dx.doi.org/10.1080/00952990.2020.1849247DOI Listing
May 2021

Add-on memantine may improve cognitive functions and attenuate inflammation in middle- to old-aged bipolar II disorder patients.

J Affect Disord 2021 01 6;279:229-238. Epub 2020 Oct 6.

Neurobiology Laboratory, NIH/NIEHS, Research Triangle Park, NC, USA.

Objectives: Chronic inflammation and neuroprogression underlie bipolar disorder (BP) and associated cognitive deficits. Memantine (MM) exerts neuroprotective effects by reducing neuroinflammation. Therefore, we investigated whether add-on low-dose MM (5 mg/day) in BP-II patients may improve cognition and inflammation.

Methods: We combined two 12-week randomized, double-blind, placebo-controlled studies (NCT01188148 and NCT03039842) for analysis. Each participant was allocated to the MM or placebo group. Symptom severity, neuropsychological tests, and the cytokine plasma levels [tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukin-8 (IL-8), transforming growth factor-β1 (TGF-β1), and brain-derived neurotrophic factor (BDNF)] were evaluated at baseline and endpoint. A subgroup analysis of middle- to old-aged BP-II patients was also performed.

Results: We recruited 155 BP-II patients (23 of which were middle- to old-aged) for the MM group and 170 patients (20 of which were middle- to old-aged) for the placebo group. Add-on MM did not result in significant improvements in cognitive functions in all BP-II patients, but a group difference in TNF-α levels was found in the MM group (P=0.04). Specifically, in middle- to old-aged BP-II patients, there was a significant time and group interaction effect on omission T-scores, hit reaction time T-scores, and hit reaction time standard error T-scores on continuous performance tests (CPTs) in the MM group (P=0.007, 0.02, and 0.01, respectively), and a decrease in plasma TNF-α levels (P=0.04).

Limitations: The sample size of middle- to old-aged BP-II patients were limited.

Conclusion: Add-on MM may attenuate inflammation in BP-II and improve cognition in middle- to old-aged BP-II patients.
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http://dx.doi.org/10.1016/j.jad.2020.10.003DOI Listing
January 2021

Effects of mood episodes and comorbid anxiety on neuropsychological impairment in patients with bipolar spectrum disorder.

Brain Behav 2020 11 30;10(11):e01813. Epub 2020 Aug 30.

Department of Psychiatry, National Cheng Kung University, Tainan City, Taiwan.

Objectives: Cases of patients with bipolar disorder (BD) having neuropsychological impairment have been reported, although inconsistently. The possibility of comorbidity with anxiety disorder (AD) has been suggested. The association between mood episodes and AD comorbidity on neuropsychological performance is unclear and thus was investigated in the current study.

Methods: All participants were informed about and agreed to participate in this study. Patients with BD were recruited from outpatient and inpatient settings, and healthy controls (HCs) were recruited as a comparison group. Six hundred and twenty-eight participants (175 HCs and 453 BD-56 BDI and 397 BDII) were studied based on their current mood episode, namely, depressive (BD ), manic/hypomanic (BDm), mixed (BDmix), and euthymic (BDeu), compared with/without AD comorbidity (164 with AD).

Results: Compared to HCs, all BD groups had significantly more impaired neuropsychological profiles, but the BDeu group was found to have less impairment in memory and executive function than the episodic BD groups. The percentage of AD comorbidity in BDd, BDm, BDmix, and BDeu was 33.9%, 40.3%, 33.0%, and 35.6%, respectively (χ  = 1.61, p > .05). The results show that AD plays a different role in neuropsychological impairment across various mood episodes in BD.

Conclusion: Memory impairment and executive dysfunction may be state-like cognitive phenotypes and are affected by AD comorbidity during mixed and depressive episodes in BD, while sustained attention deficiencies are more like trait markers, regardless of mood episodes, and persist beyond the course of the illness. The AD comorbidity effect on attentional deficit is greater when suffering from a manic episode.
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http://dx.doi.org/10.1002/brb3.1813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667309PMC
November 2020

Supratentorial and Infratentorial Lesions in Spinocerebellar Ataxia Type 3.

Front Neurol 2020 3;11:124. Epub 2020 Mar 3.

Brain Research Center, National Yang-Ming University, Taipei, Taiwan.

Spinocerebellar ataxia type 3 (SCA) is a cerebellum-dominant degenerative disorder that is characterized primarily by infratentorial damage, although less severe supratentorial involvement may contribute to the clinical manifestation. These impairments may result from the efferent loss of the cerebellar cortex and degeneration of the cerebral cortex. We used the three-dimensional fractal dimension (3D-FD) method to quantify the morphological changes in the supratentorial regions and assessed atrophy in the relatively focal regions in patients with SCA3. A total of 48 patients with SCA3 and 50 sex- and age-matched healthy individuals, as the control group, participated in this study. The 3D-FD method was proposed to distinguish 97 automatic anatomical label regions of gray matter (left cerebrum: 45, right cerebrum: 45, cerebellum: 7) between healthy individuals and patients with SCA3. Patients with SCA3 exhibited reduced brain complexity within both the traditional olivopontocerebellar atrophy (OPCA) pattern and specific supratentorial regions. The study results confirmed the extensive involvement of extracerebellar regions in SCA3. The atrophied regions of SCA3 in infratentorial and supratentorial cortex showed a wide range of overlapped areas as in two functional cortexes, namely cerebellum-related cortex and basal ganglia-related cortex. Our results found that the atrophy of the SCA3 are not only limited in the infratentorial regions. Both cerebellar related cortex and basal ganglia related cortex were affected in the disease process of SCA3. Our findings might correlate to the common symptoms of SCA3, such as ataxia, Parkinsonism, dysarthria, and dysmetria. SCA3 should no longer be considered a disease limited to the cerebellum and its connections; rather, it should be considered a pathology affecting the whole brain.
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http://dx.doi.org/10.3389/fneur.2020.00124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062793PMC
March 2020

Combination of dextromethorphan and memantine in treating bipolar spectrum disorder: a 12-week double-blind randomized clinical trial.

Int J Bipolar Disord 2020 Mar 2;8(1):11. Epub 2020 Mar 2.

Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70428, Taiwan.

Background: The aim of this study is to determine whether adding combination of agents with anti-inflammatory and neurotrophic effects is more efficacious than mood stabilizer alone in improving clinical symptoms, plasma brain-derived neurotrophic factor (BDNF), cytokine levels, and metabolic profiles in patients with bipolar spectrum disorder.

Methods: In a randomized, double-blind, controlled 12-week clinical trial, patients with moderate mood symptoms (HDRS ≥ 18 or YMRS ≥ 14) were recruited. The patients were randomly assigned to a group while still undergoing regular valproate (VPA) treatments: VPA + dextromethorphan (DM) (30 mg/day) + memantine (MM) (5 mg/day) (DM30 + MM5) (n = 66), VPA + DM (30 mg/day) (DM30) (n = 69), VPA + MM (5 mg/day) (MM5) (n = 66), or VPA + Placebo (Placebo) (n = 69). Symptom severity, immunological parameters [plasma tumor necrosis factor (TNF)-α and C-reactive protein (CRP)] and plasma brain-derived neurotrophic factor (BDNF) were regularly examined. Metabolic profiles [cholesterol, triglycerides, glycosylated hemoglobin (HbA1C), fasting serum glucose, body mass index (BMI)] were measured at baseline and at 2, 8, and 12 weeks.

Results: Depression scores were significantly (P = 0.03) decreases and BDNF levels significantly (P = 0.04) increased in the DM30 + MM5 group than in the Placebo group. However, neither depressive scores nor BDNF levels were significantly different between the DM30, MM5, and Placebo groups. Changes in certain plasma cytokine and BDNF levels were significantly correlated with metabolic parameters.

Conclusion: We concluded that add-on DM30 + MM5 was significantly more effective than placebo for clinical symptoms and plasma BDNF levels. Additional studies with larger samples and mechanistic studies are necessary to confirm our findings. Trial registration NCT03039842 (https://register.clinicaltrials.gov/). Trial date was from 1 Jan 2013 to 31 December 2016 in National Cheng Kung University Hospital. Registered 28 February 1 2017-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03039842?term=NCT03039842&rank=1.
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http://dx.doi.org/10.1186/s40345-019-0174-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049537PMC
March 2020

Serum miRNA as a possible biomarker in the diagnosis of bipolar II disorder.

Sci Rep 2020 01 24;10(1):1131. Epub 2020 Jan 24.

Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

The diagnosis of Bipolar II disorder (BD-II) is currently based on the patients' description of symptoms and clinical behavioral observations. This study explored the possibility of miRNA in peripheral blood (serum) as a specific biomarker for BD-II. We identified 6 candidate miRNAs to differentiate BD-II patients from controls using next-generation sequencing. We then examined these candidate miRNAs using real-time PCR in the first cohort (as training group) of 79 BD-II and 95 controls. A diagnostic model was built based on these candidate miRNAs and then tested on an individual testing group (BD-II: n = 20, controls: n = 20). We found that serum expression levels of miR-7-5p, miR-23b-3p, miR-142-3p, miR-221-5p, and miR-370-3p significantly increased in BD-II compared with controls in the first cohort, whereas that of miR-145-5p showed no significant difference. The diagnostic power of the identified miRNAs was further analyzed using receiver-operating characteristic (ROC). Support vector machine (SVM) measurements revealed that a combination of the significant miRNAs reached good diagnostic accuracy (AUC: 0.907). We further examined an independent testing group and the diagnostic power reached fair for BD-II (specificity = 90%, sensitivity = 85%). We constructed miRNA panels using SVM model, which may aid in the diagnosis for BD-II.
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http://dx.doi.org/10.1038/s41598-020-58195-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981268PMC
January 2020

Dextromethorphan Protect the Valproic Acid Induced Downregulation of Neutrophils in Patients with Bipolar Disorder.

Clin Psychopharmacol Neurosci 2020 Feb;18(1):145-152

Department of Psychiatry, National Cheng Kung University Hospital, Tainan, Taiwan, ROC.

Objective: Valproic acid (VPA) is an anticonvulsant and commonly long term used as a mood stabilizer for patients with mood disorders. However its chronic effects on the hematological changes were noticed and need to be further evaluated. In this study, we evaluated, in Taiwanese Han Chinese patients with bipolar disorders (BD), the chronic effects of VPA or VPA plus dextromethorphan (DM) on the hematological molecules (white blood cell [WBCs], red blood cells [RBCs], hemoglobin, hematocrit, and platelets).

Methods: In a 12-week, randomized, double-blind study, we randomly assigned BD patients to one of three groups: VPA plus either placebo (VPA+P, n = 57) or DM (30 mg/day, VPA+DM30, n = 56) or 60 mg/day (VPA+DM60, n = 53). The Young Mania Rating Scale and Hamilton Depression Rating Scale were used to evaluate symptom severity, and the hematological molecules were checked.

Results: Paired test showed that the WBC, neutrophils, platelets and RBCs were significantly lowered after 12 weeks of VPA+P or VPA+DM30 treatment. VPA+DM60 represented the protective effects in the WBCs, neutrophils, and RBCs but not in the platelets. We further calculated the changes of each hematological molecules after 12 weeks treatment. We found that combination use of DM60 significantly improved the decline in neutrophils induced by the long-term VPA treatment.

Conclusion: Hematological molecule levels were lower after long-term treatment with VPA. VPA+DM60, which yielded the protective effect in hematological change, especially in the neutrophil counts. Thus, DM might be adjunct therapy for maintaining hematological molecules in VPA treatment.
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http://dx.doi.org/10.9758/cpn.2020.18.1.145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006988PMC
February 2020

Gene: Its Effects on the Neuropsychological Functions in Patients with Opioid Use Disorder Undergoing Methadone Maintenance Treatment.

Clin Psychopharmacol Neurosci 2020 Feb;18(1):136-144

Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan.

Objective: Patients with opioid use disorder (OUD) have impaired attention, inhibition control, and memory function. The aldehyde dehydrogenase () gene has been associated with OUD and gene polymorphisms may affect aldehyde metabolism and cognitive function in other substance use disorder. Therefore, we aimed to investigate whether genotypes have significant effects on neuropsychological functions in OUD patients undergoing methadone maintenance therapy (MMT).

Methods: OUD patients undergoing MMT were investigated and followed-up for 12 weeks. gene polymorphisms were genotyped. Connors' Continuous Performance Test (CPT) and the Wechsler Memory Scale-Revised (WMS-R) were administered at baseline and after 12 weeks of MMT. Multivariate linear regressions and generalized estimating equations (GEEs) were used to examine the correlation between the genotypes and performance on the CPTs and WMS-R.

Results: We enrolled 86 patients at baseline; 61 patients completed the end-of-study assessments. The GEE analysis showed that, after the 12 weeks of MMT, OUD patients with the + ( inactive) genotypes had significantly higher commission error T-scores (= 0.03), significantly lower hit reaction time T-scores (= 0.04), and significantly lower WMS-R visual memory index scores (= 0.03) than did patients with the ( active) genotype.

Conclusion: OUD patients with the inactive genotypes performed worse in cognitive domains of attention, impulse control, and memory than did those with the active genotype. We conclude that the gene is important in OUD and is associated with neuropsychological performance after MMT.
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http://dx.doi.org/10.9758/cpn.2020.18.1.136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006970PMC
February 2020

Correlation between interleukin-6 levels and methadone maintenance therapy outcomes.

Drug Alcohol Depend 2019 11 30;204:107516. Epub 2019 Aug 30.

Neurobiology Laboratory, NIH/NIEHS, Research Triangle Park, 111 T.W. Alexander Drive, N.C. 27709, USA.

Background: The outcome of methadone maintenance therapy (MMT) varies in each patient with opioid use disorder (OUD). Opioid abuse activates proinflammatory processes by increasing cytokine production and impairing neurotrophic factor expression, and possibly leads to a vicious cycle that hinders recovery. Therefore, we investigated whether markers of inflammation and neurotrophic expression correlate with the MMT outcomes in OUD patients.

Method: We investigated OUD patients undergoing MMT and followed them up for 12 weeks. We measured plasma tumor necrosis factor (TNF)-α, C-reactive protein (CRP), interleukin (IL)-6, IL-1β, transforming growth factor (TGF)-β1, brain-derived neurotrophic factor (BDNF), urinary morphine tests, and plasma morphine levels at baseline and on weeks 1, 4, 8, and 12 during MMT. Multiple linear regressions and generalized estimating equations (GEEs) were used to examine the correlation between the cytokine and BDNF levels and MMT outcomes.

Results: We initially enrolled 104 patients, but only 78 patients completed end-of-study assessments. Plasma levels of CRP, TGF-β1, and BDNF fell during MMT. Plasma IL-6 levels were significantly associated with plasma morphine levels (P = 0.005) and urinary morphine-positive () results (P = 0.04), and significantly associated with poor compliance (P = 0.009) and early dropout from MMT (P = 0.001). However, other cytokine and BDNF levels were not consistently associated with MMT outcomes.

Conclusion: Higher IL-6 levels were associated with poor MMT outcomes. Additional studies on regulating IL-6 expression to improve treatment outcomes in OUD patients might be warranted.
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http://dx.doi.org/10.1016/j.drugalcdep.2019.06.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077753PMC
November 2019

AtJ3, a specific HSP40 protein, mediates protein farnesylation-dependent response to heat stress in Arabidopsis.

Planta 2019 Nov 15;250(5):1449-1460. Epub 2019 Jul 15.

Department of Life Sciences, National Central University, 300 Jhong-Da Road, Jhong-Li District, Taoyuan City, 32001, Taiwan.

Main Conclusion: Despite AtJ3 and AtJ2 sharing a high protein-sequence identity and both being substrates of protein farnesyltransferase (PFT), AtJ3 but not AtJ2 mediates in Arabidopsis the heat-dependent phenotypes derived from farnesylation modification. Arabidopsis HEAT-INTOERANT 5 (HIT5)/ENHANCED RESPONSE TO ABA 1 (ERA1) encodes the β-subunit of the protein farnesyltransferase (PFT), and the hit5/era1 mutant is better able to tolerate heat-shock stress than the wild type. Given that Arabidopsis AtJ2 (J2) and AtJ3 (J3) are heat-shock protein 40 (HSP40) homologs, sharing 90% protein-sequence identity, and each contains a CaaX box for farnesylation; atj2 (j2) and atj3 (j3) mutants were subjected to heat-shock treatment. Results showed that j3 but not j2 manifested the heat-shock tolerant phenotype. In addition, transgenic j3 plants that expressed a CaaX- abolishing J3 construct maintained the same capacity to tolerate heat shock as j3. The basal transcript levels of HEAT-SHOCK PROTEIN 101 (HSP101) in hit5/era1 and j3 were higher than those in the wild type. Although the capacities of j3/hsp101 and hit5/hsp101 double mutants to tolerate heat-shock stress declined compared to those of j3 and hit5/era1, they were still greater than that of the wild type. These results show that a lack of farnesylated J3 contributes to the heat-dependent phenotypes of hit5/era1, in part by the modulation of HSP101 activity, and also indicates that (a) mediator(s) other than J3 is (are) involved in the PFT-regulated heat-stress response. In addition, because HSP40s are known to function in dimer formation, bimolecular fluorescence complementation experiments were performed, and results show that J3 could dimerize regardless of farnesylation. In sum, in this study, a specific PFT substrate was identified, and its roles in the farnesylation-regulated heat-stress responses were clarified, which could be of use in future agricultural applications.
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http://dx.doi.org/10.1007/s00425-019-03239-7DOI Listing
November 2019

Quality function deployment modified for the food industry: An example of a granola bar.

Food Sci Nutr 2019 May 3;7(5):1746-1753. Epub 2019 Apr 3.

Department of Food Science National Taiwan Ocean University Keelung Taiwan.

Applying quality function deployment (QFD) in the food industry is complex. The objective of this study was to provide a modified QFD approach to facilitate its use and test it on a granola bar. A 7-step model is proposed (modified from the 9-step sensory attributes model) incorporating competitive analysis to acquire final importance ratings of customer needs, the application of fuzzy logic in surveys and interviews, and replacing precise value of relative technical ratings by priority rankings. The 7-step model starts with understanding customer needs (WHATs) and prioritizing their importance based on the customer survey and competitive analysis, followed by identification of product's sensory attributes (HOWs) and the strength of their relationship with customer needs. Lastly, relative technical ratings-to develop priority rankings for the product development team-are determined based on the degree of importance of the WHATs and the strength of the relationships between the WHATs and the HOWs. Testing the 7-step model on granola bars showed that the relative technical ratings reflected the majority of customer needs and the importance they attached to those needs.
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http://dx.doi.org/10.1002/fsn3.1014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526655PMC
May 2019

Intra- and Inter-Modular Connectivity Alterations in the Brain Structural Network of Spinocerebellar Ataxia Type 3.

Entropy (Basel) 2019 Mar 23;21(3). Epub 2019 Mar 23.

Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan.

In addition to cerebellar degeneration symptoms, patients with spinocerebellar ataxia type 3 (SCA3) exhibit extensive involvements with damage in the prefrontal cortex. A network model has been proposed for investigating the structural organization and functional mechanisms of clinical brain disorders. For neural degenerative diseases, a cortical feature-based structural connectivity network can locate cortical atrophied regions and indicate how their connectivity and functions may change. The brain network of SCA3 has been minimally explored. In this study, we investigated this network by enrolling 48 patients with SCA3 and 48 healthy subjects. A novel three-dimensional fractal dimension-based network was proposed to detect differences in network parameters between the groups. Copula correlations and modular analysis were then employed to categorize and construct the structural networks. Patients with SCA3 exhibited significant lateralized atrophy in the left supratentorial regions and significantly lower modularity values. Their cerebellar regions were dissociated from higher-level brain networks, and demonstrated decreased intra-modular connectivity in all lobes, but increased inter-modular connectivity in the frontal and parietal lobes. Our results suggest that the brain networks of patients with SCA3 may be reorganized in these regions, with the introduction of certain compensatory mechanisms in the cerebral cortex to minimize their cognitive impairment syndrome.
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http://dx.doi.org/10.3390/e21030317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7514800PMC
March 2019

Memory Impairment and Plasma BDNF Correlates of the Polymorphism in Patients With Bipolar II Disorder.

Front Genet 2018 27;9:583. Epub 2018 Nov 27.

Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Studies suggest that a functional polymorphism of brain-derived neurotrophic factor (BDNF), polymorphism affects cognitive functions, however, the effect is unclear in bipolar II (BD-II) disorder. We used the Wechsler Memory Scale-third edition (WMS-III), the presence of the polymorphism, and plasma concentrations of BDNF to investigate the association between memory impairment and BDNF in BD-II disorder. We assessed the memory functions of 228 BD-II patients and 135 healthy controls (HCs). BD-II patients had significantly lower scores on five of the eight WMS-III subscales. In addition to education, the BDNF polymorphism were associated with the following subscales of WMS-III, auditory delayed memory, auditory delayed recognition memory and general memory scores in BD-II patients, but not in HC. Moreover, BD-II patients with the -homozygote scored significantly higher on the visual immediate memory subscale than did those with the and polymorphisms. The significantly positive effect of the -homozygote did not have a significantly positive effect on memory in the HC group, however. We found no significant association between BDNF polymorphisms and plasma concentrations of BDNF. The plasma BDNF was more likely to be associated with clinical characteristics than it was with memory indices in the BD-II group. The impaired memory function in BD-II patients might be dependent upon the association between the polymorphism and peripheral BDNF levels.
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http://dx.doi.org/10.3389/fgene.2018.00583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277750PMC
November 2018

Characterization of a lytic vibriophage VP06 of Vibrio parahaemolyticus.

Res Microbiol 2019 Jan - Feb;170(1):13-23. Epub 2018 Aug 2.

Institute of Chemistry, Academia Sinica, Taipei, 115, Taiwan, ROC. Electronic address:

Vibrio parahaemolyticus is a human enteropathogenic bacterium and is also pathogenic to shrimp and finfish. In a search for a biocontrol agent for V. parahaemolyticus and other pathogenic Vibrio species, a lytic phage VP06 was isolated from oyster using V. parahaemolyticus as the host. VP06 is a Siphoviridae phage with a polyhedral head and a long tail. The genome sequence of VP06 was 75,893 nucleotides in length and the G + C content was 49%; a total of 101 CDSs were identified in VP06, of which 39 exhibited functional domains/motifs. The genomic sequence of VP06 is similar to those of a lytic Vibrio vulnificus phage SSP002 and a temperate V. parahaemolyticus phage vB_VpaS_MAR10, although VP06 has distinct features in the CDS arrangement and 14 unique CDSs. Phylogenetic analysis revealed that VP06, SSP002 and vB_VpaS_MAR10 belong to a novel genus cluster of Siphoviridae phages. This phage lysed 28.1% of various Vibrio strains, and the efficiency of plating method revealed that VP06 was highly effective in lysing strains of Vibrio alginolyticus, Vibrio azureus, Vibrio harveyi and V. parahaemolyticus. The properties of VP06, including its broad range of hosts and resistance to environmental stresses, indicate that it may be a candidate biocontrol agent.
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http://dx.doi.org/10.1016/j.resmic.2018.07.003DOI Listing
February 2019

Correlation of cytokines, BDNF levels, and memory function in patients with opioid use disorder undergoing methadone maintenance treatment.

Drug Alcohol Depend 2018 10 25;191:6-13. Epub 2018 Jul 25.

Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 70428, Taiwan; Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 70428, Taiwan; Beijing YiNing Hospital, No. 9 Minzhuang Road, Haidian District, Beijing 100195, China; Center for Neuropsychiatric Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan.

Background: Patients with opioid use disorder (OUD) show memory deficiencies and impaired treatment outcomes. Emerging evidence suggests that opioid abuse activates proinflammatory processes by increasing cytokine production and impairing neuroprotection, which damages the memory function in OUD patients. Therefore, we investigated whether plasma-based inflammatory and neurotrophic markers correlate with memory function in OUD patients.

Method: OUD patients undergoing methadone maintenance therapy (MMT) were investigated and followed up for 12 weeks. Plasma tumor necrosis factor (TNF)-α, C-reactive protein (CRP), interleukin (IL)-6, transforming growth factor (TGF)-β1, brain-derived neurotrophic factor (BDNF) levels, and Wechsler Memory Scale-Revised (WMS-R) scores were assessed at baseline and after 12 weeks of MMT. Multiple linear regressions and generalized estimating equations (GEEs) were used to examine the correlation between cytokines and memory performance.

Results: We enrolled 89 patients at baseline; 47 patients completed the end-of-study assessments. Although Pearson correlations showed that CRP and TGF-β1 levels were significantly, negatively associated with some memory indices, the results were not significant after correction. The GEE results, controlled for several confounding factors and multiple testing, showed that changes in TNF-α levels were negatively correlated with changes in the visual memory index (P = 0.01), and that changes in IL-6 levels were negatively correlated with changes in the verbal memory index (P = 0.009).

Conclusion: Memory performance, TNF-α, and IL-6 levels in OUD patients were negative correlated. Additional studies on regulating TNF-α and IL-6 expression to improve memory function in OUD patients might be warranted.
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http://dx.doi.org/10.1016/j.drugalcdep.2018.06.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487886PMC
October 2018

Add-On Memantine Treatment for Bipolar II Disorder Comorbid with Alcohol Dependence: A 12-Week Follow-Up Study.

Alcohol Clin Exp Res 2018 06 17;42(6):1044-1050. Epub 2018 May 17.

Department of Psychiatry , College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan.

Background: Bipolar disorder (BD), especially BD-II, is frequently comorbid with alcohol dependence. Because BD-II and alcohol dependence are neurodegenerative disorders, agents with anti-inflammatory and neurotrophic effects might provide effective therapy. We investigated whether add-on memantine to regular valproic acid treatment ameliorated clinical symptoms, reduced alcohol use, and cytokine levels, and increased plasma brain-derived neurotrophic factor (BDNF) in BD-II patients with comorbid alcohol dependence.

Methods: In a single-arm 12-week clinical trial, BD-II patients with comorbid alcohol dependence (n = 45) undergoing regular valproic acid treatments were given add-on memantine (5 mg/d). Symptom severity, alcohol use, cytokine (plasma tumor necrosis factor-α and C-reactive protein [CRP], transforming growth factor-β1 [TGF-β1], interleukin-8 [IL-8], IL-10), and plasma BDNF levels were regularly assessed.

Results: Mean within-group decreases in Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) scores, alcohol use, CRP, BDNF, and IL-8 levels were significantly different from baseline after 12 weeks of treatment. We found no significant correlation between alcohol use levels and changes in HDRS or YMRS scores. The correlation between reduced alcohol use and reduced TGF-β1 level was significant (B = 0.003, p = 0.019).

Conclusions: BD-II comorbid with alcohol dependence might benefit from add-on memantine treatment, which significantly reduced clinical severity, alcohol use, and plasma cytokine levels, and increased BDNF levels.
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http://dx.doi.org/10.1111/acer.13640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473794PMC
June 2018

FGF21 Is Associated with Metabolic Effects and Treatment Response in Depressed Bipolar II Disorder Patients Treated with Valproate.

Int J Neuropsychopharmacol 2018 04;21(4):319-324

Department of Psychiatry, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Background: Patients with bipolar disorder are at high risk of metabolic disturbance after mood stabilizer treatment. However, the mediators linking the two conditions remain unknown. In this study, we investigated whether fibroblast growth factor-21 (FGF21) was associated with metabolic effects and treatment response in depressed bipolar disorder patients.

Methods: We recruited 78 community-dwelling controls and 137 bipolar disorder patients; the latter were interviewed using the Chinese Version of the Modified Schedule of Affective Disorder and Schizophrenia-Life Time. Upon study entry, the bipolar disorder patients were all in a major depressive status, with 17-item Hamilton Depression Rating Scale (HDRS) scores >15. They received valproate (500-1000 mg daily) for 12 weeks, and fluoxetine 20 mg daily was permitted to treat depressive symptoms. Fasting plasma level of FGF21, lipid profiles, and body weight were collected at baseline and after 12 weeks of treatment.

Results: At baseline, the demographic characteristics, FGF21 level, and metabolic indices did not differ significantly between the controls and bipolar disorder patients. After 12 weeks of treatment, the FGF21 level (167.7±122.0 to 207.1±162.3 pg/mL, P=.001), body weight and waist circumference had increased significantly (P<.001 and P=.028, respectively). Moreover, the change in FGF21 level was significantly correlated with the changes in HDRS score (r=0.393, P=.002), total cholesterol (r=-0.344, P=.008), and low-density lipoprotein (r=-0.347, P=.007).

Conclusions: The central and peripheral mediating effects of FGF21 on bipolar disorder depression treatment might be opposite. High peripheral FGF21 levels might link regulation of metabolic effect and resistance to treatment in bipolar disorder.
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http://dx.doi.org/10.1093/ijnp/pyx093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888470PMC
April 2018

The aldehyde dehydrogenase 2 polymorphisms on neuropsychological performance in bipolar II disorder with or without comorbid anxiety disorder.

PLoS One 2018 9;13(2):e0192229. Epub 2018 Feb 9.

Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Anxiety disorders (ADs), the most common comorbid illnesses with bipolar disorder (BP) has been reported to associate with dopamine system. Dopamine, metabolized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenase 2 (ALDH2), and the distribution of the ALDH2*1/*1, and ALDH2*1/*2+ALDH*2/*2 alleles in the Han Chinese general population is relatively equal. The association between dopamine metabolic enzymes and cognitive performance in patients with bipolar II disorder (BP-II) comorbid with AD is unclear. This study proposed to explore the role of ALDH2 polymorphisms on neuropsychological performance between BP-II comorbid with or without AD. One hundred ninety-seven BP-II patients with and without a comorbid AD were recruited and compared with 130 healthy controls (HCs). A polymerase chain reaction and a restriction fragment length polymorphism analysis were used to determine genotypes for ALDH2, and study participants underwent neuropsychological tests. An interaction between AD comorbidity and the ALDH2 polymorphisms was found in different domain of cognitive dysfunction in the BP-II patients. The ALDH2 polymorphisms might have different effects on the neuropsychological performance of BP-II patients with and without comorbid AD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192229PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806854PMC
April 2018

More inflammation but less brain-derived neurotrophic factor in antisocial personality disorder.

Psychoneuroendocrinology 2017 Nov 5;85:42-48. Epub 2017 Aug 5.

Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Addiction Research Center, National Cheng Kung University, Tainan, Taiwan; Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan. Electronic address:

Antisocial personality disorder (ASPD) is highly comorbid with substance use disorders (SUDs). We hypothesize that chronic neuroinflammation and the loss of neurotrophic factors prompts the pathogenesis of both disorders. We used ELISA to measure plasma levels of proinflammatory (tumor necrosis factor-α [TNF-α], C-reactive protein [CRP]) and anti-inflammatory factors (transforming growth factor-β1 [TGF-β1] and interleukin-10 [IL-10]), and brain-derived neurotrophic factor (BDNF) in male patients with ASPD (n=74), SUDs (n=168), ASPD comorbid with SUDs (ASPD+SUDs) (n=438), and Healthy Controls (HCs) (n=81). A multivariate analysis of covariance (MANCOVA) controlled for possible confounders was used to compare cytokines and BDNF levels between groups. The results of MANCOVA adjusted for age showed a significant (p<0.001) main effect of diagnosis on inflammatory factors and BDNF expression in these groups. ASPD, SUDs, and ASPD+SUDs patients had significantly (p<0.001) higher TNF-α levels but lower TGF-β1 and BDNF levels. SUDs and ASPD+SUDs patients had higher IL-10 levels than did ASPD patients and HCs. There was no difference in IL-10 levels between HCs and ASPD. Moreover, subgrouping SUDs and ASPD±SUDs into opioid use disorder (OUD) and other SUDs groups showed that the IL-10 levels were specifically higher in OUD and ASPD±OUD groups than other SUDs (P≤0.001). We conclude that uncontrolled inflammation and losing neurotrophic factors, with or without comorbid SUDs, underlies ASPD. IL-10 expression might be more specifically associated with OUD.
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http://dx.doi.org/10.1016/j.psyneuen.2017.08.006DOI Listing
November 2017

ALDH2 modulated changes in cytokine levels and cognitive function in bipolar disorder: A 12-week follow-up study.

Aust N Z J Psychiatry 2018 07 4;52(7):680-689. Epub 2017 Aug 4.

5 Department of Psychiatry, National Cheng Kung University Hospital, Tainan, Taiwan.

Objectives: We investigated the association of the aldehyde dehydrogenase 2 ( ALDH2) polymorphism (rs671), which is involved with the dopaminergic function, and with changes in cytokine levels and cognitive function, in a 12-week follow-up study in patients with bipolar disorder.

Methods: Patients with a first diagnosis of bipolar disorder were recruited. Symptom severity and levels of plasma cytokines (tumor necrosis factor α, C-reactive protein, interleukin 6 and transforming growth factor β1) were examined during weeks 0, 1, 2, 4, 8 and 12. Neurocognitive function was evaluated at baseline and endpoint. The ALDH2 polymorphism genotype was determined.

Results: A total of 541 patients with bipolar disorder were recruited, and 355 (65.6%) completed the 12-week follow-up. A multiple linear regression analysis showed a significant ( p = 0.000226) association between the ALDH2 polymorphism and changes in C-reactive protein levels. Different aspects of cognitive function improved in patients with different ALDH2 genotypes. Only patients with the ALDH2*1*1 genotype showed significant correlations between improvement of cognitive function and increased transforming growth factor -β1.

Conclusion: The ALDH2 gene might influence changes in cytokine levels and cognitive performance in patients with bipolar disorder. Additionally, changes in cytokine levels and cognitive function were correlated only in patients with specific ALDH2 genotypes.
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http://dx.doi.org/10.1177/0004867417720517DOI Listing
July 2018

Long-term heroin use was associated with the downregulation of systemic platelets, BDNF, and TGF-β1, and it contributed to the disruption of executive function in Taiwanese Han Chinese.

Drug Alcohol Depend 2017 10 27;179:139-145. Epub 2017 Jul 27.

Graduate Institute of Medicine and M.Sc. Program in Tropical Medicine, College of Medicine, Kaohsiung Medical University (KMU), Kaohsiung, Taiwan; Department of Medical Research, KMU Hospital, Kaohsiung, Taiwan; Department of Psychiatry, National Cheng Kung University (NCKU) Hospital, Tainan, Taiwan. Electronic address:

Background: Long-term heroin addicts have low plasma brain-derived neurotrophic factor (BDNF) levels. However, the mechanisms and effects of systemic disturbances of BDNF caused by heroin remain unclear.

Objective: Blood platelet might be a source of neurotrophic factors like BDNF and transforming growth factor (TGF)-β1. Thus, we investigated the effects of heroin on platelets, BDNF and TGF-β1, the association between blood platelets, BDNF, TGF-β1, and executive function in long-term heroin addicts.

Methods: We enrolled 170 heroin addicts and 141 healthy controls. We measured their plasma BDNF and TGF-β1 levels and counted their platelets, red and white blood cells. The Wisconsin Card Sorting Test (WCST) was used to assess their executive function.

Results: Plasma BDNF and TGF-β1 levels were significantly downregulated in long-term heroin addicts. BDNF, TGF-β1, and platelet levels were lower in patients who had used heroin for more than 6 years than in those who had used it for less than 6 years. Lower plasma BDNF and TGF-β1 levels were highly correlated with the changes in platelet counts. In the WCST, the number of trials needed to complete the first category were negatively associated with platelet counts and BDNF levels.

Conclusions: In long-term heroin addicts, lower platelet counts contributed to lower plasma BDNF and TGF-β1 levels, which, in turn, contributed to the disruption of executive function after long-term heroin use. Neurotrophic- and platelet-protective agents might provide a useful research focus for heroin addiction therapy.
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http://dx.doi.org/10.1016/j.drugalcdep.2017.06.035DOI Listing
October 2017
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