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The intricate processes of microbiota-gut-brain communication in modulating human cognition and emotion, especially in the context of mood disorders, have remained elusive. Here we performed faecal metagenomic, serum metabolomics and neuroimaging studies on a cohort of 109 unmedicated patients with depressed bipolar disorder (BD) patients and 40 healthy controls (HCs) to characterise the microbial-gut-brain axis in BD. Across over 12,000 measured metabolic features, we observed a large discrepancy (73.54%) in the serum metabolome between BD patients and HCs, spotting differentially abundant microbial-derived neuroactive metabolites including multiple B-vitamins, kynurenic acid, gamma-aminobutyric acid and short-chain fatty acids. These metabolites could be linked to the abundance of gut microbiota presented with corresponding biosynthetic potentials, including Akkermansia muciniphila, Citrobacter spp. (Citrobacter freundii and Citrobacter werkmanii), Phascolarctobacterium spp., Yersinia spp. (Yersinia frederiksenii and Yersinia aleksiciae), Enterobacter spp. (Enterobacter cloacae and Enterobacter kobei) and Flavobacterium spp. Based on functional neuroimaging, BD-related neuroactive microbes and metabolites were discovered as potential markers associated with BD-typical features of functional connectivity of brain networks, hinting at aberrant cognitive function, emotion regulation, and interoception. Our study combines gut microbiota and neuroactive metabolites with brain functional connectivity, thereby revealing potential signalling pathways from the microbiota to the gut and the brain, which may have a role in the pathophysiology of BD.

Jing Lu,1 Shangda Li,1 Haimei Li,1 Tingting Mou,1 Lihong Zhou,2 Bochao Huang,1 Manli Huang,1 Yi Xu1 1The Key Laboratory of Mental Disorder Management in Zhejiang Province, Department of Psychiatry, First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang University Brain Research Institute, Hangzhou, Zhejiang Province, People’s Republic of China; 2Institute of Criminal Science and Technology, Hangzhou Public Security Bureau, Hangzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Yi Xu; Manli HuangThe Key Laboratory of Mental Disorder Management in Zhejiang Province, Department of Psychiatry, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qing Chun Road, Hangzhou 310003, People’s Republic of ChinaTel/fax +86-571-8723-5995Email xuyizju@zju.edu.cn; huangmanli@zju.edu.cnPurpose: There is growing evidence showing that inflammatory cytokines and neuropeptides may be involved in the pathophysiology of suicidal behavior. However, studies have yielded contradictory data, and no biological markers that help predict suicide have been identified. This study aimed to identify biological patterns, such as NPY, IL-1β and hypocretin plasma levels, in people who died by suicide.Patients and methods: Twenty-two people who died by suicide compared with 22 controls matched for age and sex were studied. In suicide and control subjects, we estimated the levels of NPY, IL-1β and hypocretin in plasma using enzyme-linked immunosorbent assay. The data are presented as the median (25th–75th percentile).Results: We found (1) a significant elevation in plasma NPY levels in suicide subjects versus control subjects (suicide: 11.38 (9.380–16.55); controls: 8.95 (7.590–10.93); P=0.013), and plasma NPY concentrations were approximately 62% higher in suicide subjects than those in control subjects; (2) a significant decrease in plasma IL-1β concentrati

Fen Pan,1,2 Da Li,1,2 Xiaojing Wang,3 Shaojia Lu,1,2 Yi Xu,1,2 Manli Huang1,2 1Department of Mental Health, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, People’s Republic of China; 2The Key Laboratory of Mental Disorder’s Management of Zhejiang Province, Hangzhou 310003, People’s Republic of China; 3School of Medicine, Zhejiang University, Hangzhou 310000, People’s Republic of China Background: A high proportion of adolescents with major depressive disorder currently do not respond to conventional treatment. Repetitive transcranial magnetic stimulation (rTMS) is a promising treatment for major depressive disorder. Case: We report on 3 cases of adolescents with suicidal ideation receiving 7 daily 10 Hz left prefrontal rTMS combined with pharmacotherapy treatment over 1 week for major depressive episode. The left dorsolateral prefrontal cortex was identified using magnetic resonance imaging-guided neuronavigation prior to stimulation. The suicidal ideation of these patients lessened significantly following rTMS treatment. Regarding adverse effects, symptoms of hypomania occurred in two patients since day 4, but no other side effects were found. Conclusion: Neuronavigation-guided high-dose rTMS may be an effective and feasible treatment option for depressive adolescents with suicidal ideation. Caution over treatment-emergent mania/hypomania associated with rTMS is required. Keywords: neuronavigation, repetitive transcranial magnetic stimulation, depressive adolescents, suicidal ideation

Jinfeng Duan,1,2 Chengming Lao,3,4 Jingkai Chen,1,2 Fen Pan,1,2 Chenlin Zhang,3 Weijuan Xu,1,2 Weihua Zhou,1,2 Jianbo Hu,1,2 Desheng Shang,1 Manli Huang,1,2 Yi Xu1,2 1Department of Psychiatry, First Affiliated Hospital, College of Medicine, Zhejiang University, The Key Laboratory of Mental Disorder’s Management of Zhejiang Province, Hangzhou, People’s Republic of China; 2Brain Research Institute of Zhejiang University, Hangzhou, People’s Republic of China; 3College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 4Yiwu Mental Health Center, Yiwu, People’s Republic of China Abstract: Memantine, an N-methyl-D-aspartate receptor antagonist, is a well-established treatment option for moderate-to-severe cognitive impairment related to Alzheimer disease. Recently, growing evidence has indicated memantine might also be effective in treatment of affective disorders. The common drug-induced adverse events of memantine include confusion, dizziness, drowsiness, headache, insomnia, and agitation. Herein, we presented a case of a 73-year-old female patient with vascular neurocognitive disorder, who developed a manic episode after taking memantine. Keywords: memantine, depression, dementia, manic episode

Fen Pan,1,2 Shangda Li,3 Haimei Li,3 Yi Xu,1,2 Manli Huang1,2 1Department of Psychiatry, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China; 2The Key Laboratory of Mental Disorder’s Management of Zhejiang Province, Hangzhou 310003, China; 3School of Medicine, Zhejiang University, Hangzhou 310000, China Background: Paroxysmal kinesigenic dyskinesia (PKD) is characterized by sudden episodes of involuntary movements. PKD is a very rare movement disorder, and correct clinical diagnosis is often a challenge. Case: We present the case of a 23-year-old female with PKD. The patient showed episodes of twisting movements for 3 years. The symptoms lasted for about 5–10 minutes and subsided spontaneously. She was diagnosed as having epilepsy, and depressive and anxiety disorders successively. However, her symptoms did not alleviate after taking sodium valproate and antidepressants. Though there were no mutations in her PRRT2 gene, carbamazepine was used for treatment and was effective in controlling her symptoms. Conclusion: The clinical features of PKD patients are not always typical; therefore, it is important to distinguish PKD from the other subtypes of paroxysmal dyskinesia and psychogenic disorders. Keywords: paroxysmal kinesigenic dyskinesia, misdiagnosis, PRRT2 gene

In depression, disrupted circadian rhythms reflect abnormalities in the central circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN). Although many SCN neurons are said to be GABAergic, it was not yet known whether and how SCN GABA changes occur in the SCN in depression. We, therefore, studied GABA in the SCN in relation to the changes in arginine vasopressin (AVP), which is one of the major SCN output systems. Postmortem hypothalamus specimens of 13 subjects suffering from depression and of 13 well-matched controls were collected. Quantitative immunocytochemistry was used to analyze the protein levels of glutamic acid decarboxylase (GAD)65/67 and AVP, and quantitative in situ hybridization was used to measure transcript levels of GAD67 in the SCN. There were a significant 58% increase of SCN GAD65/67-ir and a significant 169% increase of SCN GAD67-mRNA in the depression group. In addition, there were a significant 253% increase of AVP-ir in female depression subjects but not in male depression patients. This sex difference was supported by a re-analysis of SCN AVP-ir data of a previous study of our group. Moreover, SCN-AVP-ir showed a significant negative correlation with age in the control group and in the male, but not in the female depression group. Given the crucial role of GABA in mediating SCN function, our finding of increased SCN GABA expression may significantly contribute to the disordered circadian rhythms in depression. The increased SCN AVP-ir in female-but not in male-depression patients-may reflect the higher vulnerability for depression in women.

In depression, disrupted circadian rhythms reflect abnormalities in the central circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN). Although many SCN neurons are said to be GABAergic, it was not yet known whether and how SCN GABA changes occur in the SCN in depression. We, therefore, studied GABA in the SCN in relation to the changes in arginine vasopressin (AVP), which is one of the major SCN output systems. Postmortem hypothalamus specimens of 13 subjects suffering from depression and of 13 well-matched controls were collected. Quantitative immunocytochemistry was used to analyze the protein levels of glutamic acid decarboxylase (GAD)65/67 and AVP, and quantitative in situ hybridization was used to measure transcript levels of GAD67 in the SCN. There were a significant 58% increase of SCN GAD65/67-ir and a significant 169% increase of SCN GAD67-mRNA in the depression group. In addition, there were a significant 253% increase of AVP-ir in female depression subjects but not in male depression patients. This sex difference was supported by a re-analysis of SCN AVP-ir data of a previous study of our group. Moreover, SCN-AVP-ir showed a significant negative correlation with age in the control group and in the male, but not in the female depression group. Given the crucial role of GABA in mediating SCN function, our finding of increased SCN GABA expression may significantly contribute to the disordered circadian rhythms in depression. The increased SCN AVP-ir in female-but not in male-depression patients-may reflect the higher vulnerability for depression in women.