Orexin/hypocretin and major psychiatric disorders.

Orexin A and B, also known as hypocretin 1 and 2, are excitory neuropeptides synthesized in the perifornical and lateral hypothalamic areas. Following their discovery in 1998, orexins are now known to be involved in feeding, sleep, stress response, and reward processing. Most importantly, orexin deficiency has been linked to narcolepsy, a neurological sleep-wake disorder. Patients with narcolepsy also present overlapping symptoms with psychiatric disorders, such as anxiety and depressed mood, and even hallucinations, which often lead to misdiagnosis in the initial assessment. In this article, we aim to review studies of the orexin system associated with the three major psychiatric disorders: schizophrenia, major depressive disorder (MDD), and bipolar disorder. In addition to animal and clinical reports, studies of the orexin system in treatment, symptoms and side effects would also be reviewed. Thus far, relatively robust evidence suggests a connection of the orexin system with MDD. Findings of orexin involvement in schizophrenia are inconsistent and only studies in bipolar disorder are limited. While the orexin system might not be firmly associated with diagnosis, it may be useful to target specific symptom within the diagnosis or treatment, such as insomnia, weight gain and polydipsia.

Corrigendum: Isobaric Tags for Relative and Absolute Quantitation Identification of Blood Proteins Relevant to Paroxetine Response in Patients With Major Depressive Disorder.

[This corrects the article DOI: 10.3389/fpsyt.2022.577857.].

Isobaric Tags for Relative and Absolute Quantitation Identification of Blood Proteins Relevant to Paroxetine Response in Patients With Major Depressive Disorder.

Objectives: Isobaric tags for relative and absolute quantitation (iTRAQ) is a proteomic investigation that could be utilized for rapid identification and quantification of proteins, which we would use to identify differentially expressed proteins in treatment responsive patients with major depressive disorder (MDD). Methods: Six treatment responsive patients of MDD were recruited, and their peripheral blood mononuclear cell (PBMC) were collected before and after 4 weeks of paroxetine treatment. iTRAQ and Mascot search engine were used to detect differentially expressed proteins, which were then validated by Western blot. Results: Two thousand one hundred and fifty three proteins were screened, and seven proteins showed differences of more than two-fold and 62 proteins with a differences of less than two-fold. Six proteins with commercially available antibodies were identified, and were validated by Western blot in 10 paroxetine responsive MDD patients. Putative hydroxypyruvate isomerase (HYI), eukaryotic translation initiation factor 4H (eIF4H), and RNA binding motif 8A (RBM8A) had statistically significant differences before and after treatment in the validation. Data are available via ProteomeXchange with identifier PXD028947. Conclusions: By using iTRAQ and Western blot, we were able to identify HYI, eIF4H, and RAM8a to be the potential predictors of paroxetine treatment response in patients with MDD. This finding could help establish future individualized medicine.

SIGIRR and TNFAIP3 Are Differentially Expressed in Both PBMC and TNF-α Secreting Cells of Patients With Major Depressive Disorder.

Background: Major depressive disorder (MDD) is associated with the activation of the immune/inflammatory system. TNF-α is associated with MDD and poor treatment response. Toll-like receptors (TLR) are responsible in innate immune response, and is associated with MDD and antidepressant response. Some negative regulators of TLR pathway such as SOCS1, TOLLIP, SIGIRR, TNFAIP3, and MyD88s, are reported to be differentially expressed in the peripheral blood samples of patients of MDD. Methods: We recruited patients with MDD and healthy controls, collect their demographic data, and measured their mRNA levels of negative TLR regulators, using peripheral blood mononuclear cells (PBMC) and isolated TNF-α secreting cells. Clinical symptoms were evaluated using Halmiton Depression Rating Scale (Ham-D). Some patients were evaluated again after 4 weeks of antidepressant treatment. Results: Forty-seven patients with MDD and 52 healthy controls were recruited. Between the PBMC samples of 37 MDD patients and 42 controls, mRNA levels of SOCS1, SIGIRR, TNFAIP3, and MyD88s were significantly different. Between TNF-α secreting cells of 10 MDD patients and 10 controls, mRNA levels of SIGIRR and TNFAIP3 were significantly different. Change of Ham-D score only correlated significantly with TOLLIP mRNA level after treatment. Conclusion: SIGIRR and TNFAIP3, two negative regulators of TLR immune response pathways, were differentially expressed in both PBMC and TNF-α secreting cells of patients with MDD as compared to healthy controls. The negative regulations of innate immune response could contribute to the underlying mechanism of MDD.

Brain-derived neurotrophic factor and mental disorders.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that modulates neuroplasticity in the brain, and is one of the most widely investigated molecule in psychiatric disorders. The researches of BDNF emcompassed the advance of investigative techniques of past decades. BDNF researches ranged from protein quantilization, to RNA expression measurements, to DNA sequencing, and lately but not lastly, epigenetic studies. In this review, we will briefly address findings on BDNF protein levels, mRNA expression, Val66Met polymorphism, and epigenetic modifications, in schizophrenia, major depressive disorder (MDD), and bipolar disorder.

Abnormal Brain-Derived Neurotrophic Factor Exon IX Promoter Methylation, Protein, and mRNA Levels in Patients with Major Depressive Disorder.

Brain-derived neurotrophic factor (BDNF) exon IX promoter methylation levels, serum BDNF protein levels, and serum mRNA levels were investigated in patients with major depressive disorder (MDD) and healthy controls. Over two years, 51 patients with MDD and 62 healthy controls were recruited. Peripheral blood was drawn from all participants to analyze the BDNF exon IX promoter methylation levels as well as serum BDNF protein and mRNA levels, at baseline and after four weeks of antidepressant treatment. Methylation sequential analysis showed that patients with MDD (n = 39) had a higher methylation level at CpG site 217 and lower methylation levels at CpG site 327 and CpG site 362. Drug responders (n = 25) had a higher methylation level at CpG site 24 and CpG site 324 than the non-responders (n = 11). Patients with MDD had a lower serum BDNF protein and mRNA levels than the healthy controls. In conclusion, these results showed that BDNF exon IX promoter methylation levels, serum BDNF protein level, and serum BDNF mRNA level could contribute to the pathophysiology of a major depressive disorder.

Antidepressant treatment increased serum miR-183 and miR-212 levels in patients with major depressive disorder.

Major depressive disorder (MDD) had been associated with brain-derived neurotrophic factor (BDNF). Studies had shown that patients with MDD were associated with lower BDNF protein levels, which could be reversed by antidepressant treatment. BDNF expression had also been affected by a number of microRNAs (miRNA). BDNF and miRNA in MDD had been investigated widely in the recent years, but the relationships between miRNAs and antidepressants were less studied. From November 2015 to October 2017, inpatients diagnosed with MDD were recruited. Serum miR-16, miR-30, miR-34, miR-128, miR-132, miR-134, miR-182, miR-183, miR-185, miR-212 levels were measured before and after four weeks of antidepressant treatment of either selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). Thirty-three patients with MDD were recruited. After treatment, miR-183 and miR-212 levels increased significantly. In patients treated with SSRI (n = 13), miR-16 levels increased significantly after treatment. Therefore, miR-183 and miR-212 levels increased significantly after four weeks of antidepressant treatment. In the SSRI group, significantly increased miR-16 levels were found, but not in SNRI group, suggesting that different types of antidepressants might affect different sets of miRNAs.

Increased serum anti-N-methyl-D-aspartate receptor antibody immunofluorescence in psychiatric patients with past catatonia.

OBJECTIVE: Anti-N-methyl-D-aspartate receptor (NMDAR) antibody was thought to be the cause of anti-NMDAR encephalitis, with manifestations similar to catatonia and schizophrenia. Anti-NMDAR antibody in neuropsychiatric patients who had catatonia before were investigated in a follow-up evaluation. The intensity of antibody immunofluorescence was quantified and compared with healthy controls. METHOD: Nineteen patients (eight males and eleven females) agreed to be followed-up. Thirteen had the diagnosis of schizophrenia, two had the diagnosis of major depressive disorder, two had bipolar disorder, one had postpartum depression, and one had herpes simplex encephalitis. No patient had catatonia during the follow-up. Nineteen sex-matched healthy controls were recruited. RESULTS: Using Mann-Whitney U test, patients had greater intensity of anti-NMDAR antibody immunofluorescence than the healthy controls (121,979 ± 86,526 vs. 47,692 ± 26,102, p = 0.003). No correlation was found between immunofluorescence intensity and catatonia scales or symptom severity scores. Neuropsychiatric patients with past catatonia showed greater anti-NMDAR antibody response than the healthy controls. CONCLUSION: NMDAR dysfunction might play a role in the mechanism underlying catatonia. Further studies are needed to confirm this finding.

Increased serum brain-derived neurotrophic factor in male schizophrenic patients with metabolic syndrome.

Increased prevalence of metabolic syndrome was found in patients with schizophrenia. Brain-derived neurotrophic factor (BDNF) was involved in energy metabolism and the pathophysiology of schizophrenia, but differently in males and females. We aimed to investigate the serum BDNF levels in patients with schizophrenia with and without metabolic syndrome.Patients with schizophrenia were recruited. Their demographic data were collected. Metabolic profiles and serum BDNF levels were measured. Clinical symptoms were evaluated with Positive and Negative Syndrome Scale. Metabolic syndrome was determined with the criteria provided by Ministry of Health and Welfare of Taiwan. Framingham Risk Score (FRS) for estimate of 10-year risk for coronary heart disease was provided by National Institutes of Health.Of the 81 participants, 40.7% had metabolic syndrome. Those with metabolic syndrome had higher FRS. Using analysis of covariance adjusted for age and body mass index, male patients with schizophrenia with metabolic syndrome had higher serum BDNF levels than those without (4.6 ±â€Š4.7 vs 3.3 ±â€Š3.8 ng/mL, P = .022). No statistical difference was found between female patients with and without metabolic syndrome.Significant differences of serum BDNF levels were found between male patients with schizophrenia with and without metabolic syndrome, but not in females. This finding suggested the gender difference behind the mechanism of BDNF in metabolic syndrome in schizophrenia.

The Lorazepam and Diazepam Protocol for Catatonia Due to General Medical Condition and Substance in Liaison Psychiatry.

OBJECTIVE: The lorazepam-diazepam protocol had been proved to rapidly and effectively relieve catatonia in patients with schizophrenia or mood disorder. This study aims to investigate the efficacy of lorazepam-diazepam protocol in catatonia due to general medical conditions (GMC) and substance. METHOD: Patients with catatonia that required psychiatric intervention in various settings of a medical center were included. The lorazepam-diazepam protocol had been used to treat the catatonia due to GMC or substance according to DSM-IV criteria. The treatment response had been assessed by two psychiatrists. RESULTS: Eighteen (85.7%) of 21 catatonic patients due to GMC or substance became free of catatonia after the lorazepam-diazepam protocol. Five (23.8%) of the 21 patients had passed away with various causes of death and wide range of time periods after catatonia. CONCLUSION: Our results showed that the lorazepam-diazepam protocol could rapidly and effectively relieve catatonia due to GMC and substance.

TNFAIP3, a negative regulator of the TLR signaling pathway, is a potential predictive biomarker of response to antidepressant treatment in major depressive disorder.

Inflammation and abnormalities in Toll-like receptor (TLR) expression and activation have been linked to major depressive disorder (MDD). However, negative regulators of TLR pathways have not been previously investigated in this context. Here, we sought to investigate the association of depression severity, measured by the 17-item Hamilton Depression Rating Scale (HAMD-17), with mRNA expression levels of negative regulators of the TLR pathway, including SOCS1, TOLLIP, SIGIRR, MyD88s, NOD2 and TNFAIP3, in peripheral blood mononuclear cells (PBMCs) from 100 patients with MDD and 53 healthy controls, before and after treatment with antidepressants. Positive regulators of the TLR4 pathway, including Pellino 1, TRAF6 and IRAK1, were also investigated. Among all patients, MyD88s, and TNFAIP3 mRNAs were expressed at lower levels in PBMCs from patients with MDD. Multiple linear regression analyses revealed that TNFAIP3 mRNA expression before treatment was inversely correlated with severity of depression and effectively predicted improvement in HAMD-17 scores. Among 79 treatment-completers, only TNFAIP3 mRNA was significantly increased by treatment with antidepressants for 4 weeks. Treatment of human monocytes (THP-1) and mouse microglia (SIM-A9) cell lines with fluoxetine significantly increased TNFAIP3 mRNA expression and suppressed IL-6 levels. The suppressive effect of fluoxetine on IL-6 was attenuated by knockdown of TNFAIP3 expression. These findings suggest that both dysfunction of the negative regulatory system in patients with MDD and antidepressant treatment exert anti-inflammatory effects, at least in part through increased expression of the TNFAIP3 gene. They also indicate that modulating expression of the TNFAIP3 gene to rebalance TLR-mediated inflammatory signaling may be potential therapeutic strategy for treating MDD.

Brain-derived neurotrophic factor protein and mRNA levels in patients with bipolar mania - A preliminary study.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) protein or mRNA levels may be involved in the pathophysiology of bipolar disorder. However, the results were inconsistent. We aimed to simultaneously investigate the relationship of BDNF protein and mRNA levels in peripheral blood of patients with bipolar mania. METHODS: Patients with bipolar mania (n = 30) and healthy controls (n = 30) were recruited during our one-year study. Psychiatric diagnoses were made according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria. The scores of the Young Mania Rating Scale (YMRS) of patients with bipolar mania were greater than 26. All participants had peripheral blood drawn to analyze the serum BDNF protein and mRNA levels. RESULTS: Using t-test, patients with bipolar mania had a lower BDNF protein and mRNA levels than did the healthy controls (p < 0.001 and 0.049, respectively), however, the statistical significances were lost after analysis of co-variance adjusted for age and body mass index. Twenty seven out of 30 patients with bipolar mania remained in the study after the 4 weeks of mood stabilizer treatment. Patients' BDNF protein and mRNA levels did not change significantly after 4-week treatment. CONCLUSIONS: Our study found that serum BDNF protein and mRNA levels in patients with bipolar mania were lower than healthy controls, but a larger sample size will be needed to confirm this finding.

Higher blood MLL1 mRNA and BDNF promoter IV on histone H3K4me3 levels in patients with schizophrenia.

We investigated the blood levels of mixed-lineage leukemia 1 (MLL1) mRNA and BDNF (brain derived neurotrophic factor) exon IV promoter on histone Histone 3 lysine 4 trimethylation (H3K4me3) in peripheral blood of patients with schizophrenia and controls. Over one year, 36 patients with schizophrenia and 32 controls were recruited. Psychiatric diagnoses were made based on DSM-IV criteria. Higher blood MLL1 mRNA and BDNF exon IV promoter on H3K4me3 levels were noted in patients with schizophrenia than in controls. The results showed that blood MLL1 mRNA and BDNF exon IV on H3K4me3 levels might be involved in the psychopathology of schizophrenia.

Relapses and recurrences of catatonia: 30-case analysis and literature review.

OBJECTIVE: Relieving catatonia helps identify the underlying etiology and its treatment. However, catatonia may reemerge after some time, but there are few data on the relapses and recurrences of catatonia. We aimed to investigate the characteristics of patients with relapses or recurrences of catatonia as well as the efficacy of the lorazepam-diazepam protocol on them. METHODS: Patients with catatonia who had more than one episode of catatonia and were treated with the lorazepam-diazepam protocol were identified. Their medical charts were reviewed, and interview was conducted. RESULTS: Thirty patients were identified. Nineteen (63.3%) were diagnosed with schizophrenia, five (16.7%) with major depressive disorder, two (6.7%) with bipolar disorder, and four (13.3%) with general medical conditions. In the 68 relapses and relapses the lorazepam-diazepam protocol was used, full response was reported in 54 (79.4%) of them. Twelve of 19 (63.2%) patients with schizophrenia were treated with clozapine. Twenty (66.7%) out of 30 patients were maintained on oral lorazepam by the time of discharge. Literature review showed similar prevalence of schizophrenia in patients with more than one episode of catatonia, and a wide variety of treatment options. CONCLUSION: The lorazepam-diazepam protocol was mostly effective in managing relapses and recurrences of catatonia. Maintenance clozapine and oral lorazepam were beneficial in a significant number of patients.

A Case Report of Catatonia and Neuroleptic Malignant Syndrome With Multiple Treatment Modalities: Short Communication and Literature Review.

We describe a case with complicated clinical presentations who was difficult to treat. We described the possible etiologies and differential diagnosis of neuroleptic malignant syndrome (NMS), catatonia, and infection, in details. This patient was also referred to neuro-intensive care unit for extensive workup and treatments by neurologist guidelines. In addition, we also used lorazepam-diazepam protocol and antipsychotics, but both failed to completely relieve her symptoms. She eventually responded to electroconvulsive therapy (ECT).A 60-year-old female patient with schizophrenia was diagnosed to suspected pneumonia, urinary tract infection, and retarded catatonia at first. The brain computed tomography revealed no significant finding. She developed NMS caused by the administration of low-dose quetiapine (200 mg) after carbamazepine was discontinued. The Francis-Yacoub NMS rating scale (F-Y scale) total score was 90. We utilized lorazepam-diazepam protocol and prescribed bromocriptine and amantadine, but NMS was not improved. Meanwhile, we arranged the brain magnetic resonance imaging to survey the physical problem, which revealed agenesis of septum pellucidum and dilated lateral ventricles. She was then transferred to the neuro-intensive care unit on the 15th hospital day for complete study. The results of cerebrospinal fluid study and electroencephalography were unremarkable. She was transferred back to psychiatric ward on the 21st hospital day with residual catatonic and parkinsonian symptoms of NMS, and the F-Y scale total score was 63. Finally, her residual catatonic condition that followed NMS got improved after 11 sessions of ECT. On the 47th hospital day, the F-Y scale total score was 9.This report underscores that the ECT is an effective treatment for a patient of NMS when other treatments have failed.

Advances in biomarkers of major depressive disorder.

Major depressive disorder (MDD) is characterized by mood, vegetative, cognitive, and even psychotic symptoms and signs that can cause substantial impairments in quality of life and functioning. Biomarkers are measurable indicators that could help diagnosing MDD or predicting treatment response. In this chapter, lipid profiles, immune/inflammation, and neurotrophic factor pathways that have long been implicated in the pathogenesis of MDD are discussed. Then, pharmacogenetics and epigenetics of serotonin transport and its metabolism pathway, brain-derived neurotrophic factor, and abnormality of hypothalamo-pituitary-adrenocortical axis also revealed new biomarkers. Lastly, new techniques, such as proteomics and metabolomics, which allow researchers to approach the studying of MDD with new directions and make new discoveries are addressed. In the future, more data are needed regarding pathophysiology of MDD, including protein levels, single nucleotide polymorphism, epigenetic regulation, and clinical data in order to better identify reliable and consistent biomarkers for diagnosis, treatment choice, and outcome prediction.

Lorazepam-diazepam protocol for catatonia in schizophrenia: a 21-case analysis.

OBJECTIVES: Catatonia is a unique clinical phenomenon characterized by concurrent motor, emotional, vegetative and behavioral signs. Benzodiazepines (BZD) and electroconvulsive therapy (ECT) can rapidly relieve catatonic signs. The lorazepam-diazepam protocol presented here has been proven to relieve catatonia in schizophrenia within a day. METHODS: From July 2002 to August 2011, schizophrenic patients requiring psychiatric intervention for catatonia in Kaohsiung Chang Gung Memorial Hospital were studied by medical chart review. The study used the Bush-Francis Catatonia Rating Scale (BFCRS). Patients receiving the lorazepam-diazepam protocol were identified. RESULTS: The survey included 21 patients (eight males and 13 females) with a mean age of 30.3 ± 12.6 years. Mean duration of schizophrenia was 4.7 ± 5.6 years. Thirteen (61.9%) patients responded within 2 h, 18 (85.7%) responded within one day, and all became catatonia-free within a week. Mean BFCRS score was 9.9 ± 3.0 before treatment. Patients that responded with a single intramuscular lorazepam injection had mean BFCRS score of 8.9 ± 2.8, significantly lower than the mean score (11.6 ± 2.5) of the rest of the patients (p = 0.034). CONCLUSIONS: The lorazepam-diazepam protocol can rapidly relieve retarded catatonia in schizophrenia. Most patients became catatonia-free within one day but some may require up to a week. ECT should be considered if the protocol fails.

Increased high-sensitivity C-reactive protein levels in Taiwanese schizophrenic patients.

INTRODUCTION: Schizophrenia is associated with the activation of the immune/inflammatory system. C-reactive protein (CRP), a positive acute phase protein, may be associated with schizophrenia and antipsychotic treatment. METHODS: The serum high-sensitivity CRP (hsCRP) levels of 36 schizophrenic patients undergoing clozapine, olanzapine or risperidone treatment and 36 sex-matched healthy subjects were collected. The difference in hsCRP levels between the schizophrenic and the control groups was estimated using ancova. anova was performed to examine the differences in the hsCRP levels between three antipsychotic groups (clozapine, olanzapine and risperidone). RESULTS: ancova adjusted for age and body mass index (BMI) revealed a significant increase in the hsCRP levels in the schizophrenic group (1.4 mg/L, SD =1.5 mg/L) in comparison with the control group (0.9 mg/L, SD = 1.4 mg/L) (P = 0.013). anova revealed no statistical difference of age, BMI and hsCRP in three antipsychotic groups (P = 0.83, 0.90 and 0.71, respectively). DISCUSSION: The elevation of CRP level is seen in chronic schizophrenia under antipsychotic treatment; however, studies with a larger sample size are required to confirm these results.

Rapid relief of catatonia in mood disorder by lorazepam and diazepam.

BACKGROUND: Catatonia has risks of severe morbidity and mortality and needs early treatment. In this study, we investigated more patients to discuss the efficacy of this treatment in patients with major depressive disorder (MDD) or bipolar I disorder (BPI). METHODS: During a period of 9 years, we identified 12 catatonic patients with mood disorder, with MDD (n = 10) and BPI (n = 2) in the emergency department, inpatient and outpatient units of a general hospital. The patients received intramuscular injection (IMI) of 2 mg lorazepam once or twice during the first 2 h. If intramuscular lorazepam failed, intravenous dripping (IVD) of 10 mg diazepam in 500 mL normal saline every 8 h for 1 day was prescribed. RESULTS: Eight patients had full remission of catatonia after receiving one dose of 2 mg lorazepam IMI. Two patients needed two doses of 2 mg lorazepam IMI. Two patients with BPI recovered from catatonia using one dose of 10 mg diazepam IVD over 8 h after they failed to respond to two doses of 2 mg lorazepam IMI. The response rate to lorazepam IMI was 83.3%. All catatonic features remitted in 24 h with 100% response rate. CONCLUSIONS: The lorazepam-diazepam treatment strategy is a safe and effective method to relieve catatonia in mood disorder within 1 day. Psychiatrist consultation is helpful for final diagnosis and rapid treatment of catatonia.