Molecular mechanisms of quetiapine bidirectional regulation of bipolar depression and mania based on network pharmacology and molecular docking: Evidence from computational biology.

BACKGROUND: Quetiapine monotherapy is recommended as the first-line option for acute mania and acute bipolar depression. However, the mechanism of action of quetiapine is unclear. Network pharmacology and molecular docking were employed to determine the molecular mechanisms of quetiapine bidirectional regulation of bipolar depression and mania. METHODS: Putative target genes for quetiapine were collected from the GeneCard, SwissTargetPrediction, and DrugBank databases. Targets for bipolar depression and bipolar mania were identified from the DisGeNET and GeneCards databases. A protein-protein interaction (PPI) network was generated using the String database and imported into Cytoscape. DAVID and the Bioinformatics platform were employed to perform the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the top 15 core targets. The drug-pathway-target-disease network was constructed using Cytoscape. Finally, molecular docking was performed to evaluate the interactions between quetiapine and potential targets. RESULTS: Targets for quetiapine actions against bipolar depression (126 targets) and bipolar mania (81 targets) were identified. Based on PPI and KEGG pathway analyses, quetiapine may affect bipolar depression by targeting the MAPK and PI3K/AKT insulin signaling pathways via BDNF, INS, EGFR, IGF1, and NGF, and it may affect bipolar mania by targeting the neuroactive ligand-receptor interaction signaling pathway via HTR1A, HTR1B, HTR2A, DRD2, and GRIN2B. Molecular docking revealed good binding affinity between quetiapine and potential targets. LIMITATIONS: Pharmacological experiments should be conducted to verify and further explore these results. CONCLUSIONS: Our findings suggest that quetiapine affects bipolar depression and bipolar mania through distinct biological core targets, and thus through different mechanisms. Furthermore, our results provide a theoretical basis for the clinical use of quetiapine and possible directions for new drug development.

Safety and Efficacy of High-Dose Vitamin B6 as an Adjunctive Treatment for Antipsychotic-Induced Hyperprolactinemia in Male Patients With Treatment-Resistant Schizophrenia.

This study aimed to investigate the safety and efficacy of high-dose vitamin B6 (vB6) as an adjunct treatment for antipsychotic-induced hyperprolactinemia (AIHP) in male patients with treatment-resistant schizophrenia (TRS). In this randomized double-blinded controlled study, patients were randomized (1:1) into a control group given aripiprazole (ARI; 10 mg/day; n = 100) or an intervention group given vB6 (300 mg/12 h for 16 weeks; n = 100). Prolactin levels, psychotic symptoms [Positive and Negative Syndrome Scale (PANSS)], cognitive function [MATRICS Consensus Cognitive Battery (MCCB)], liver function, kidney function, growth hormone level, micronutrient levels, blood lipids, and adverse secondary effects (ASEs)[Treatment Emergent Symptom Scale (TESS) and Barnes-Akathisia scale] were monitored. After a 16-week treatment period, the vB6 group showed a 68.1% reduction in serum prolactin levels (from 95.52 ± 6.30 µg/L to 30.43 ± 18.65 µg/L) while the ARI group showed only a 37.4% reduction (from 89.07 ± 3.59 µg/L to 55.78 ± 7.39 µg/L). During weeks 1-4, both treatments reduced prolactin similarly. Subsequently, the ARI effect plateaued, while the vB6 effect remained robust. The vB6 group showed better alleviation of psychotic symptoms and cognitive impairment. No serious ASEs were observed; ASEs were more frequent in the ARI group. AIHP reduction efficacy of vB6 was associated with baseline prolactin and triglyceride levels, total vB6 dosage, and education level. In conclusion, compared with the ARI group, TRS patients given vB6 showed better attenuation of AIHP, lower ASE scores, and greater improvements in clinical symptoms and cognitive impairments. These results support further consideration of vB6 as a putative treatment for AIHP. Trial Registration: ChiCTR1800014755.

Mechanism differences between typical yin and typical yang personality individuals assessed by Five-Pattern Personality Inventory (FPPI): Evidence from resting-state brain functional networks.

BACKGROUND: Most studies assessing brain-personality mechanisms have used Western personality questionnaires. However, Western personality questionnaires may not objectively reflect the personality characteristics of individuals in Eastern cultures such as China. Hence, we adopted the functional magnetic resonance imaging (fMRI) and the Chinese localized scale, FPPI, to explore the brain mechanisms differences of typical yin and typical yang personalities of individuals in China. METHODS: 30 typical yin personality participants (TYI) and 34 typical yang personality participants (TYA) were enrolled according to the FPPI. The group differences of the functional brain networks among 90 specific brain regions were mapped using fMRI data and then analyzed by the conventional network metrics (CNM) and frequency subgraph mining (FSM). RESULTS: The CNM and FSM differences between two typical personality groups were traced to the frontal, temporal, and parietal cortices. The yin group, reflecting the rich emotions and feelings of individuals, showed higher betweenness centrality (BCi) and nodal efficiency (Ei) values in putamen and middle frontal gyrus. The yang group, reflecting active behaviors and tendency to adapting to the changing surroundings, showed higher BCi and Ei values in precuneus, posterior cingulate gyrus, and inferior parietal lobule, brain areas in the default mode network (DMN). CONCLUSION: These results supplied evidence for the neurobiological differences between typical yin and typical yang personality participants based on Chinese culture. These results also provide a new perspective to help researchers understand brain mechanism differences between yin and yang personality groups in the Chinese culture.

Effects of ketamine on circadian rhythm and synaptic homeostasis in patients with treatment-resistant depression: A protocol for mechanistic studies of its rapid and sustained antidepressant actions in humans.

BACKGROUND: The breakthrough discovery has been made that a single dose of ketamine, an N-methyl-D-aspartate receptor antagonist, achieves rapid and sustained (~7 days) antidepressant activity in patients with major depressive disorder (MDD). This discovery has ushered in an exciting era of research and brought new hope for patients with MDD. However, the mechanisms underlying the specific antidepressant actions of ketamine in humans remain to be elucidated. OBJECTIVES: This study protocol was designed to test the main hypothesis that ketamine could rapidly reverse depression- and stress-associated synaptic loss and deficits in resting-state functional connectivity and that this action could be affected by circadian rhythm, in patients with treatment-resistant depression. METHODS/STUDY DESIGN: In this clinical study, adults (aged 18-65 years) with treatment-resistant depression will be randomized to intravenous administration of placebo (control group) or ketamine (0.5 mg/kg body weight) at 11 a.m. (daytime group), or 6 p.m. (nighttime group) for 24 weeks. The primary outcome will be the change from baseline to 24 weeks in the total Montgomery-Asberg Depression Rating Scale score. Brain imaging, sleep, and genetic studies, including functional magnetic resonance imaging, positron emission tomography, polysomnography, and genetic analyses, will be performed to examine whether and how ketamine can rapidly reverse deficits in synaptic function and to identify objective markers for the assessment of ketamine infusion therapy for treatment-resistant depression. CONCLUSIONS: This clinical study protocol is the first, to our knowledge, to describe the prospective testing of the hypothesis that daytime and nighttime administrations of ketamine would have different antidepressant effects. The brain imaging, sleep, and genetic findings from patients with treatment-resistant depression are expected to shed new light on the mechanisms of ketamine and its interaction with target sites in the brain, which can be used for objective evaluation of the efficacy of ketamine.

Auditory verbal hallucination and the auditory network: From molecules to connectivity.

Auditory verbal hallucinations (AVHs) frequently occur across multiple psychiatric diseases especially in schizophrenia (SCZ) patients. Functional imaging studies have revealed the hyperactivity of the auditory cortex and disrupted auditory-verbal network activity underlying AVH etiology. This review will firstly summarize major findings from both human AVH patients and animal models, with focuses on the auditory cortex and associated cortical/sub-cortical areas. Besides mesoscale connectivity or activity data, structure and functions at synaptic level will be discussed, in conjunction with molecular mechanisms. We have summarized major findings for the pathogenesis of AVH in SCZ patients, with focuses in the auditory cortex and prefrontal cortex (PFC). Those discoveries provide explanations for AVH from different perspectives including inter-regional connectivity, local activity in specific areas, structure and functions of synapse, and potentially molecular targets. Due to the uniqueness of AVH in humans, full replica using animals seems impossible. However, we can still extract useful information from animal SCZ models based on the disruption of auditory pathway during AVH episodes. Therefore, we will further interpolate the synaptic structures and molecular targets, whose dysregulation in SCZ models may be highly related with AVH episodes. As the last part, implications for future development of treatment strategies will be discussed.

Altered Coupling Between Resting-State Cerebral Blood Flow and Functional Connectivity in Schizophrenia.

Background: Respective changes in resting-state cerebral blood flow (CBF) and functional connectivity in schizophrenia have been reported. However, their coupling alterations in schizophrenia remain largely unknown. Methods: 89 schizophrenia patients and 90 sex- and age-matched healthy controls underwent resting-state functional MRI to calculate functional connectivity strength (FCS) and arterial spin labeling imaging to compute CBF. The CBF-FCS coupling of the whole gray matter and the CBF/FCS ratio (the amount of blood supply per unit of connectivity strength) of each voxel were compared between the 2 groups. Results: Whole gray matter CBF-FCS coupling was decreased in schizophrenia patients relative to healthy controls. In schizophrenia patients, the decreased CBF/FCS ratio was predominantly located in cognitive- and emotional-related brain regions, including the dorsolateral prefrontal cortex, insula, hippocampus and thalamus, whereas an increased CBF/FCS ratio was mainly identified in the sensorimotor regions, including the putamen, and sensorimotor, mid-cingulate and visual cortices. Conclusion: These findings suggest that the neurovascular decoupling in the brain may be a possible neuropathological mechanism of schizophrenia.

Cerebral blood flow alterations specific to auditory verbal hallucinations in schizophrenia.

BackgroundAuditory verbal hallucinations (AVHs) have been associated with deficits in auditory and speech-related networks. However, the resting-state cerebral blood flow (CBF) alterations specific to AVHs in schizophrenia remain unknown.AimsTo explore AVH-related CBF alterations in individuals with schizophrenia.MethodIn total, 35 individuals with schizophrenia with AVHs, 41 individuals with schizophrenia without AVHs and 50 controls underwent arterial spin labelling magnetic resonance imaging. The CBF differences were voxel-wise compared across the three groups.ResultsWe found AVH-specific CBF increase in the right superior temporal gyrus and caudate, and AVH-specific CBF decrease in the bilateral occipital and left parietal cortices. We also observed consistent CBF changes in both schizophrenia subgroups (i.e. those with and without AVHs) including decreased CBF in the bilateral occipital regions, the left lateral prefrontal and insular cortices, and the right anterior cingulate cortex and increased CBF in the bilateral lateral temporal regions and putamen, the left middle cingulate cortex and the right thalamus.ConclusionsThe AVH-specific CBF increases in the auditory and striatal areas and CBF reductions in the visual and parietal areas suggest that there exists a CBF redistribution associated with AVHs.

The application and efficacy of combined neurofeedback therapy and imagery training in adolescents with Tourette syndrome.

We aimed to examine the effectiveness of combined neurofeedback therapy and imagery training in adolescent patients with refractory Tourette syndrome. Two patients, aged respectively 14 and 16 years, had been treated with haloperidol and tiapride; however, this medication was ineffective and accompanied by intolerable side effects. In this study, the patients completed 80 sessions of neurofeedback treatment followed by imagery training. The patients were assessed with behavior rating scales both before and after the treatment as well as during follow-up examinations to evaluate the effect of the combined therapy. Patients showed significant improvement in motor tic and vocal tic symptoms, exemplified by a reduction in the frequency and intensity of tics, indicating that neurofeedback, together with imagery training, has a positive therapeutic effect on adolescent patients with medication-refractory Tourette syndrome.

A randomised controlled trial of combined EEG feedback and methylphenidate therapy for the treatment of ADHD.

PURPOSE: To evaluate the efficacy of combined methylphenidate and EEG feedback treatment for children with ADHD. METHODS: Forty patients with ADHD were randomly assigned to the combination group (methylphenidate therapy and EEG feedback training) or control group (methylphenidate therapy and non-feedback attention training) in a 1:1 ratio using the double-blind method. These patients, who met the DSM-IV diagnostic criteria and were aged between 7 and 16 years, had obtained optimal therapeutic effects by titrating the methylphenidate dose prior to the trial. The patients were assessed using multiple parameters at baseline, after 20 treatment sessions, after 40 treatment sessions, and in 6-month follow-up studies. RESULTS: Compared to the control group, patients in the combination group had reduced ADHD symptoms and improved in related behavioural and brain functions. CONCLUSION: The combination of EEG feedback and methylphenidate treatment is more effective than methylphenidate alone. The combined therapy is especially suitable for children and adolescents with ADHD who insufficiently respond to single drug treatment or experience drug side effects.