Plasma leptin levels are lower in females, but not males, with ketamine use disorder.

Background: Ketamine has emerged as a prominent substance of misuse. Leptin, an adipocyte-derived polypeptide hormone, has been implicated in the development of addiction. Sex-specific changes in leptin levels have been demonstrated following acute ketamine administration; the persistence of long-term ketamine use on leptin levels is uncertain.Objectives: To assess the sex-difference of leptin levels, and their persistence, in individuals with ketamine use disorder (KUD) compared to healthy controls.Methods: Plasma leptin levels were measured in 62 healthy controls (37 males, 25 females) and 68 participants with KUD (50 males, 18 females) on the first day (baseline) and after 1 and 2 weeks of abstinence. As leptin levels are affected by body mass index (BMI), BMI-adjusted leptin (leptin/BMI ratio) was also examined. Mixed model for repeated measures was used to examine changes after ketamine abstinence.Results: Compared to same-sex controls, female, but not male, participants with KUD demonstrated lower leptin levels and leptin/BMI ratio at baseline, week 1, and week 2 (leptin levels: p = .001, 0.006 and 0.032, respectively; leptin/BMI ratio: p = .004, 0.022, and 0.09, respectively). Repeated measures showed that leptin levels and the leptin/BMI ratio increased after 2 weeks of abstinence in male participants with KUD (p = .002 and 0.011, respectively), but females did not show such an increase (p > .05).Conclusions: Sex-specific differences were observed in leptin levels and the leptin/BMI ratio in individuals with KUD compared to controls. Lower leptin levels in females with KUD persisted after 2 weeks of abstinence.

The effects of Lactobacillus plantarum PS128 in patients with major depressive disorder: an eight-week double-blind, placebo-controlled study.

Major depressive disorder (MDD) is a complex mental disorder, potentially linked to the gut-microbiota-brain axis. Probiotics like Lactobacillus plantarum PS128 (PS128) may improve depressive symptoms by modulating the gut microbiota based on our previous open trial. We conducted an 8-week double-blind, placebo-controlled trial to investigate the impact of PS128 on depression severity, markers of inflammation and gut permeability, and the gut microbiota composition in 32 patients with MDD with stable antidepressant treatment but moderate symptom severity. Following the 8-week intervention, both the Hamilton Depression Rating Scale-17 score (HAMD), and Depression and Somatic Symptoms Scale (DSSS) showed a significant decrease in both groups (p<0.001). However, there was no significant difference in the change of depression severity between groups (p=0.203). Moreover, alterations in serum levels of high sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-α, and intestinal fatty acid binding protein, as well as changes in the gut microbiota composition, did not exhibit significant differences before and after intervention or between the groups. In comparison to the placebo group, our study did not find significant effects of PS128 on depressive symptoms, biomarkers of inflammation and gut permeability, and the overall gut microbiota composition. Nonetheless, we observed a potential impact of PS128 on the symbiosis of specific taxa. To comprehensively understand the psychophysiological effects of PS128 in patients with MDD, further research with a larger sample size is imperative.

Comorbidity of ketamine dependence with major depressive disorder increases the vulnerability to neuroaxonal pathology.

We recently demonstrated that patients with ketamine dependence (KD) have increased serum levels of neurofilament light chain (NfL), a novel marker of active neuroaxonal pathology, with NfL levels being significantly higher in those KD patients comorbid with major depressive disorder (MDD). However, considering that NfL elevation has been associated with both ketamine-related brain pathology and MDD, we could not determine whether the observed elevation of NfL levels was driven by an interaction of KD with MDD or by MDD itself. Therefore, we compared serum NfL levels between 35 patients with MDD without ketamine use (MDD group), 23 with KD without MDD (KD without MDD group), 30 KD with MDD (KD with MDD group), and 86 healthy controls (HC group). Using a 2*2 (KD*MDD) generalized linear model controlling for age, sex, body mass index, and smoking status, we found that KD and KD*MDD interactions, but not MDD factor, significantly affected NfL levels. Posthoc tests showed that the KD with MDD group had significantly higher NfL levels than all other groups. The KD without MDD group also showed higher NfL levels than the MDD and, as shown before, HC groups. The levels in MDD group were not different from the HC group. These results suggest that the interaction of KD with MDD, but not MDD alone, results in increased vulnerability to neuroaxonal pathology.

Psychophysiological Effects of Lactobacillus plantarum PS128 in Patients with Major Depressive Disorder: A Preliminary 8-Week Open Trial.

Recent studies have suggested that gut-brain axis may be one of the mechanisms of major depression disorder (MDD). The current study aimed to investigate the effects of Lactobacillus plantarum PS128 (PS128) on psychophysiology in patients with MDD. We recruited 11 patients with MDD and gave them PS128 for 8 weeks. We compared depression symptoms, serum markers of inflammation and gut permeability, and gut microbiota before and after 8-week intervention and also explored the correlations among symptoms, biomarkers, and gut microbiota. After 8-week PS128 intervention, scores of Hamilton Depression Rating Scale-17 and Depression and Somatic symptoms Scale significantly decreased. Serum levels of high sensitivity c-reactive protein, interluekin-6, and tumor necrosis factor-α, zonulin and intestinal fatty acid binding protein, and the composition of gut microbiota did not significantly change after 8-week PS128 intervention. However, we found changes of some genera were correlated with changes of symptoms and biomarkers. In conclusion, this is an open trial with small sample size and has several limitations. The results need to be verified by randomized, double-blind, placebo-controlled trial with larger sample size.

Orexin-A Levels in Relation to the Risk of Metabolic Syndrome in Patients with Schizophrenia Taking Antipsychotics.

Background: The role of orexin-A in regulating metabolic homeostasis has been recognized, but its association with antipsychotic-induced metabolic abnormalities remains unclear. We investigated the association between orexin-A levels and metabolic syndrome in patients with schizophrenia treated with clozapine or less obesogenic antipsychotics compared with nonpsychiatric controls. Methods: Plasma orexin-A levels and metabolic parameters were determined in 159 patients with schizophrenia: 109 taking clozapine; 50 taking aripiprazole, amisulpride, ziprasidone, or haloperidol; and 60 nonpsychiatric controls. Results: Orexin-A levels were significantly higher in the group taking less obesogenic antipsychotics, followed by the clozapine group and the controls (F=104.6, P<.01). Higher orexin-A levels were correlated with better metabolic profiles in the patient groups but not in the controls. Regression analyses revealed that the patients with higher orexin-A levels had significantly lower risk of metabolic syndrome (adjusted odds ratio [OR]=0.04, 95% CI: 0.01-0.38 for the 2nd tertile; OR=0.04, 95% CI: 0.01-0.36 for the 3rd tertile, compared with the first tertile), after adjustment for age, sex, smoking history, types of antipsychotics (clozapine vs less obesogenic antipsychotics), duration of antipsychotic treatment, and disease severity. Conclusions: Our results revealed that the orexin-A level was upregulated in patients with schizophrenia treated with antipsychotics, especially for the group taking less obesogenic antipsychotics. Furthermore, higher orexin-A levels were independently associated with better metabolic profiles. These observations suggest that an upregulation of orexin-A has a protective effect against the development of metabolic abnormalities in patients with schizophrenia receiving antipsychotic treatment.

Consumption of Alcoholic Energy Drinks Is Associated with Work-related Injury or Disease Among Manual Workers in Taiwan.

AIMS: Alcoholic energy drinks (AEDs) have been popular among Taiwanese manual workers. Study results concerning increased health risks of AED consumption relative to alcohol alone have been inconsistent, and the risk for potential work-related injury or disease has not been studied. Our study goal was to evaluate the association between AED consumption and work-related injury or disease in manual workers in Taiwan. METHODS: National survey data of the working population in 2007 was utilized. A total of 1192 manual workers, who drank alcohol more than once per week, were divided into AED-drinkers and non-AED drinkers. We compared AED drinking behaviors and risk of work-related injury or disease between the two groups. RESULTS: AED drinkers had a higher risk of work-related injury or disease, with an odds ratio of 1.48 (95% CI: 1.14-1.93), after controlling demographic, smoking and drinking characteristics. The presence of problem drinking (defined by CAGE score equal to or higher than two) was another risk factor of having work-related injury or disease. Compared to non-AED counterparts, AED drinkers had a significantly higher prevalence of work-related injury or disease in the strata of CAGE score of 1 and 2. CONCLUSION: AED consumers presented increased risks of work-related injury or disease compared with non-AED drinkers among manual workers in Taiwan. In order to conduct an effective intervention program to protect Taiwanese manual workers from potential risks, the reasons for this increased risk among AED drinkers need to be further studied.

Oxidative stress status in recently abstinent methamphetamine abusers.

AIM: Methamphetamine (METH) administration is associated with excessive oxidative stress. It is not known whether the systemic oxidative stress indices would alter during early abstinence in METH abusers with positive urine testing for recent METH exposure. METHODS: Sixty-four non-treatment-seeking METH abusers enrolled from a controlled environment and 60 healthy controls participated in the study. Fasting serum malondialdehyde (MDA) levels and anti-oxidant indices, including superoxide dismutase (SOD) and catalase (CAT) activity, and glutathione (GSH) levels, were measured at baseline and 2 weeks after the first measurement. We compared the differences of these oxidative stress indices between METH abusers and controls and examined the changes of the indices 2 weeks after baseline in the METH group. RESULTS: At baseline, the recently abstinent METH abusers had significantly higher MDA levels, lower SOD activity, and higher CAT activity and GSH levels compared to healthy controls. CAT and GSH values were positively correlated with MDA but negatively correlated with SOD. These oxidative stress indices did not significantly correlate with age, smoking amount, Alcohol Use Disorder Identification Test scores, or METH use variables. After 2 more weeks of abstinence, the indices did not alter nor normalize. CONCLUSION: Compared to controls, we found that METH abusers have persistently higher systemic oxidative stress throughout early abstinence. The compromised SOD as well as elevated CAT activity and GSH levels may act together as a compensatory mechanism to counteract excessive oxidative stress induced by METH. Whether the oxidative stress could improve after a longer period of abstinence needs to be examined in future studies.

Relationship between liver function and brain shrinkage in patients with alcohol dependence.

BACKGROUND: Oxidative stress has been proposed as one of the mechanisms of alcohol-induced brain shrinkage and alcohol-induced hepatotoxicity. The aim of this study was to assess the correlations between liver function and brain volume (BV) measurements in patients with alcohol dependence. METHODS: We recruited 124 patients with alcohol dependence and 111 healthy control subjects from National Institute of Health, National Institute on Alcohol Abuse and Alcoholism inpatient alcohol treatment program. Gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), as well as hematocrit (Hct) and albumin were assayed shortly after admission. Magnetic resonance imaging examination was conducted in both groups (after 3-week abstinence in the patient group). We used stepwise linear regression analyses to determine the variables most strongly correlated with brain shrinkage. RESULTS: Patients with alcohol dependence had lower BV, and greater brain shrinkage as measured by gray matter ratio (GMR), white matter ratio (WMR), brain ratio (BR), and higher cerebrospinal fluid ratio ratio (CSFR) compared with their healthy counterparts. Age and sex were significantly correlated with some BV measurements in both patient and control groups. Body mass index (BMI) was significantly correlated with CSFR, BR, GMR, and WMR; Hct with CSFR and BR; serum GGT level with BV, CSFR, BR, GMR, and WMF in the patient group. No biological variables were correlated with BV indices in the control group. In gender-stratified analysis, age was significantly correlated with brain shrinkage in male patients but not in female patients. Serum GGT level in male and female patients, Hct in male patients, and AST levels in female patients were significantly correlated with brain shrinkage. CONCLUSIONS: Our results showed that the higher levels of liver function indices, especially GGT, correlated with BV shrinkage as measured using CSFR, BR, GMR, and WMR in patients with alcohol dependence but not in controls. Serum GGT level outweighed aging effect on brain shrinkage in female patients.

Basic fibroblast growth factor inhibits p38-mediated cell differentiation and growth inhibition by activin A but not by histone deacetylase inhibitors in CML cells.

The p38 mitogen-activated protein kinase (p38) is involved in multiple cellular functions such as cell proliferation and differentiation. Previously, we found that activin A mediated hemoglobin synthesis and cell growth inhibition through p38, whereas, basic fibroblast growth factor (bFGF) inactivated p38 to antagonize the activin A effects. In this study, we selected three structurally different histone deacetylase (HDAC) inhibitors, apicidin, MS275, and sodium butyrate that activate p38, to probe the signal pathway from activin A to p38 in chronic myeloid leukemia (CML)-derived K562 cells. HDAC inhibitors and activin A showed additive p38 phosphorylation. The enhanced phosphorylation of p38 was correlated with increased cell differentiation and decreased cell proliferation. The use of p38 inhibitor SB203580 in conjunction with activin A or with the HDAC inhibitors inhibited cell differentiation and restored cell proliferation, indicating that activin A and the HDAC inhibitors exert their effects through p38 activation. However, bFGF did not affect HDAC inhibitors-induced cell differentiation or growth inhibition. Western blots showed that p38 phosphorylation remained at similar levels with or without bFGF in the presence of HDAC inhibitors. Thus, the HDAC inhibitors activate p38 in a manner different from the activin A pathway. Furthermore, mRNA expressions for activin type I, IB, II, and IIB receptors remained constant in the presence of activin A, bFGF, or both activin A and bFGF. These results indicate that bFGF does not directly act on p38 nor on the mRNA expression levels of activin receptors but inhibit activin A activation of p38 upstream of p38 in K562 cells.

Prevalence and identification of alcohol use disorders among nonpsychiatric inpatients in one general hospital.

Alcohol use disorders (AUDs) are common among inpatients in general hospitals and often cause excess mortality. This study investigates the prevalence of AUDs among nonpsychiatric inpatients in one general hospital and evaluates the ability of medical staff to identify such morbidity. A two-phase case-identification strategy was employed utilizing the Alcohol Use Disorders Identification Test as the first-phase screening tool and the Schedules for Clinical Assessment in Neuropsychiatry as the second-phase diagnostic interview. Among 538 eligible patients, a total of 422 (78.4%) completed the first-phase screening. A subsample (20%) of those screened negative and 90% of those screened positive were interviewed at the second phase. The weighted 1-year prevalence rates of alcohol abuse and alcohol dependence were 3.9% and 12.6%, respectively. The overall identification rate of AUDs by medical staff was 25.4% (0% for alcohol abuse and 30% for alcohol dependence). In conclusion, approximately one sixth of nonpsychiatric inpatients in a general hospital have AUDs and have been neglected substantially by medical staff. Implications of the findings for the prevention of AUDs and their physical complications are discussed.