Safety and tolerability of topiramate and N-acetyl cysteine combination in individuals with alcohol use disorder: a 12 week, randomized, double-blind, pilot study.

Topiramate (TPM), a GABA/glutamate modulator, has shown positive results for treating alcohol use disorder (AUD), but causes significant cognitive adverse effects. TPM causes cognitive side effects by reducing glutathione levels in the frontal lobe. N-acetyl cysteine (NAC) increases level of intracellular glutathione. We hypothesized that combining NAC with TPM may mitigate the possible cognitive side effects of TPM, as well as working synergistically in reducing alcohol consumption more efficaciously than using TPM alone. A 12-week, double-blind randomized trial assessing the effects of combining NAC (1200 mg/day) with TPM (200 mg/day) vs TPM alone (i) cognitive side effects caused by TPM, (ii) percentage of heavy drinking days (PHDD) and percentage of days abstinent (PDA) using weekly calendar, and (iii) craving outcomes using the obsessive-compulsive drinking scale. Seventeen participants were randomized into the study (nine received TPM + NAC and eight matching TPM + Placebo). Cognitive adverse events were not significantly different between the treatment arms (P = 0.581). There was no difference in PHDD (P = 0.536) and in PDA over the entire study period (P = 0.892). However, both treatment groups at study end, compared with the baseline, significantly reduced their PHDD and increased their PDA. As for cravings: TPM + NAC group has shown higher level in automaticity of drinking (P = 0.029) and interference due to drinking (P = 0.014) subscales compared with the TPM + Placebo group. No difference was observed between groups in terms of Drinking Obsessions and Alcohol Consumption subscales. This pilot study indicates that combining NAC with TPM is overall safe, but the addition of NAC has no significant benefit over placebo in the incidence of TPM-related cognitive impairment, and alcohol drinking. Furthermore, craving outcomes may become worse with the addition of NAC.

MAY PPAR GAMMA BE SIGNIFICANT IN BIPOLAR DISORDER ONLY IN THE PRESENCE OF METABOLIC SYNDROME?

BACKGROUND: Peroxisome proliferator-activated receptor γ (PPARγ) has a key role in regulating both neurogenesis and various metabolic processes, including adipogenesis and glucose homeostasis. In this study, it was aimed to compare the serum PPARγ levels and metabolic syndrome (MetS) parametres of patients with Bipolar Disorder (BD) diagnosed manic-depressive-euthymic episodes with those of healthy subjects. SUBJECTS AND METHODS: We included 121 male patients with BD type I, 44 in mania, 35 in depression and 42 in euthymic state, and 41 healthy controls. Serum PPARγ levels, inflammation indicators (CRP, neutrophil, leukocyte, and albumin) and Mets parametres were measured. RESULTS: There were no statistically significant differences between the groups in terms of PPARγ values. PPARγ serum level is highest in the control group and then euthymic, manic and depressive episodes continue to decrease, respectively. However, there was a significant difference between the depressive group with MetS and without MetS in terms of serum PPARγ levels. A statistically significant correlation was found between PPARγ and the other serum markers such as low-density lipoprotein (p=0.022), HbA1c (p=0.002), neutrophils levels (0.001), white blood cell (p=0.025), and clinical features such as age at first treatment (p=0.024), age at first episode (p=0.039), and smoking (0.013). CONCLUSIONS: We suggest that PPARγ may be a key factor in the BD depressive group with MetS. Not finding any relationship between the PPARγ levels and the episode of BD may be related with the absence of MetS in the individuals. MetS parametres must also be considered if PPARγ is to be evaluated in the future investigations.

Feasibility Pilot Study of an Opioid Helpline for Individuals at High Risk for Opioid Use Disorder.

BACKGROUND: Evidence suggests that educational interventions delivered by healthcare providers can be effective in altering patients' attitudes toward pain management and in referral to addiction treatment when appropriate. Time constraints during visits limit the delivery of such important interventions. OBJECTIVE: This study aims to explore the feasibility and perceived value of an opioid helpline that provides resources to individuals suffering from or at risk for opioid use disorder. METHODS: We developed a helpline with a toll-free number "1-877 OPIOIDS (6437)" established through the University of Virginia, which runs Monday through Friday from 8:30 am to 5 pm and is answered by a live answering service after hours. The helpline offered a range of resources including opioid pain medication education, signs of overdose or withdrawal, addiction treatment options, and connection to treatment services. The helpline was supported by outreach efforts to surrounding counties in Virginia. Questionnaires on perceived usefulness were sent to callers and providers who used or offered the helpline in their clinics. Survey data were analyzed to identify trends. RESULTS: Thirty-one consented individuals of 166 contacts were included in the study. Although participants were referred to the helpline through a variety of sources, most were referred by a physician (38.7%). Most participants rated the helpline's helpfulness with the highest satisfaction score (81.5%). Most individuals seeking addiction treatment found the helpline to be useful, whereas those referred by their respective physician to gain more information about their opioid use and prevent escalation to addiction felt it was an unnecessary step. CONCLUSIONS: Our pilot study demonstrated that a helpline could be an additional tool to combat the opioid crisis. Individual callers rated the intervention favorably. Our study shows that the most substantial area of satisfaction for our participants is being able to reach a live person when in need.

Detecting biomarkers associated with antipsychotic-induced extrapyramidal syndromes by using machine learning techniques.

BACKGROUND: Antipsychotic-associated extrapyramidal syndromes (EPS) are a common side effect that may result in discontinuation of treatment. Although some clinical features of individuals who develop specific EPSs are well defined, no specific laboratory parameter has been identified to predict the risk of developing EPS. METHODS: Three hundred and ninety hospitalizations of patients under antipsychotic medication were evaluated. Machine learning techniques were applied to laboratory parameters routinely collected at admission. RESULTS: Random forests classifier gave the most promising results to show the importance of parameters in developing EPS. Albumin has the maximum importance in the model with 4.28% followed by folate with 4.09%. The mean albumin levels of EPS and non-EPS group was 4,06 ± 0,40 and 4,24 ± 0,37 (p = 0,027) and folate level was 6,42 ± 3,44 and 7,95 ± 4,16 (p = 0,05) respectively. Both parameters showed lower levels in EPS group. CONCLUSIONS: Our results suggest that relatively low albumin and folate levels may be associated with developing EPS. Further research is needed to determine cut-off levels for these candidate markers to predict EPS.

Factors Moderating the Impact of After Death Communications on Beliefs and Spirituality.

After death communications(ADCs) are defined as perceived spontaneous contacts with living individuals by the deceased. This research presents on a subset of data from a recent large international survey of individuals who experienced ADCs and provided systematic information regarding these experiences. In our research we explore the impact of having an ADC on reported spirituality, religiosity, beliefs and attitudes about death and dying and also explore the moderating factors of this impact. We found that having an ADC was perceived as a positive life experience and that it was associated with a reduction in fear of death, belief in life after death and that the deceased could communicate with the living, and increased reported spirituality. Moderating factors include aspects of having or desiring physical contact with the deceased as well as perceiving some emotional reaction to the ADCs. Future directions for research exploration are also provided based on our findings.

Can Neutrophil-Lymphocyte Ratio Be a Useful Criterion for Neuroleptic Malignant Syndrome in the Absence of Leukocytosis?

Objective: Neuroleptic malignant syndrome (NMS) is a rare but severe side effect of antipsychotic medication. Neutrophil-lymphocyte ratio (NLR) is a simple marker used to measure systemic inflammation. Method : In this case report we explore the relationship of inflammation in the etiology of NMS. In our case involving NMS, although there was no leukocytosis, the NLR was increased up to systemic infection levels. Conclusion: We hypothesized that systemic inflammation may take a role in developing NMS. If so, NLR could be a new marker of NMS that may be able to provide more sensitive results than leukocyte levels.

Resolvin D1 as a novel anti-inflammatory marker in manic, depressive and euthymic states of bipolar disorder.

Background: Resolvin D1 (RvD1) is a soluble mediator, which is the metabolite of docosahexaenoic acid (DHA), an omega-3 fatty acid. It is thought that RvD1 may contribute to the etiology of bipolar disorder (BD) because of its anti-inflammatory and antidepressant effect. In this study, it was aimed to compare the serum RvD1 levels of patients with BD diagnosed manic-depressive-euthymic episodes with those of healthy subjects. The secondary objective of this study is to investigate the relationship between RvD1 measures and inflammatory markers.Methods: We included 121 male patients with BD type I, 44 in a mania, 35 in depression and 42 in euthymic state, and 41 healthy controls. Serum RvD1 levels and inflammation indicators (CRP, neutrophil, leukocyte, and albumin) were measured.Results: When the RvD1 values of patients were compared, the median (interquartile range) RvD1 value was 11.2 (5.2) for manic patients, 11.2 (6.6) for depressive patients, 9.6 (5.6) for euthymic patients and 8.4 (7.7) for the control group. There were statistically significant differences between the groups in terms of RvD1 values (p < .001). After adjustment for age and current state with ANCOVA, there were statistically significant differences between manic vs. control groups and depression vs. control groups (p < .001, p=.047). Also mean CRP measures (p=.029) and neutrophil counts (p=.009) were significantly correlated with log transformed RvD1 levels.Conclusions: Our results of increased anti-inflammatory RvD1 during manic and depressive states suggest RvD1 may serve as a delayed resolvent possibly improving inflammatory imbalance. Further research is needed to confirm our findings.

Clinical utility of neutrophil-lymphocyte ratio in the diagnosis of neuroleptic malignant syndrome.

Background: Neuroleptic malignant syndrome (NMS) is a life-threatening side effect of antipsychotic medication. In this study, we aimed to investigate the hypothesis of inflammation via neutrophil-lymphocyte ratio (NLR) in the etiology of NMS. Methods: In this retrospective case-control study, data were collected using digital database of Bakirköy Mental Health Research and Training State Hospital by screening NMS diagnosis according to 'International Classification of Diseases (ICD-10) code: G21.0' between the years of 2007 and 2017. We included 32 hospitalizations with the diagnosis of NMS and 31 other acute psychiatric hospitalizations without NMS of same patients. NLR was calculated as proportion of absolute neutrophil count to absolute lymphocyte count. Significance level was accepted as p < .05. Results: The mean NLR value of NMS group was 9.55 ± 5.13 and control group was 2.06 ± 0.71 (p < .001). According to ROC analysis in our study group, we found a mean NLR cutoff value ≥4 and lymphocyte percent cutoff of ≤18.4% have the probability of correctly identifying patients with NMS with the 100% sensitivity and 100% specificity. Conclusions: In this retrospective study, we considered that higher NLR value in NMS episode might be a resemblance of systemic inflammatory state. In addition, our results suggest that both NLR and lymphocyte percentage may be alternative minor criteria which are more sensitive and specific than leukocyte levels and CPK.

Serum osmolarity and blood viscosity as a potential explanation for the pathophysiology of neuroleptic malignant syndrome.

Background: Neuroleptic malignant syndrome (NMS) is a rare but life-threatening side effect. NMS patients usually develop dehydration and fluid-electrolyte imbalance. In this study, we aimed to investigate serum osmolarity and blood viscosity in patients with NMS.Methods: This was a retrospective case-control study including 32 admissions of 27 patients with the diagnosis of NMS. As a control group, 31 non-NMS episodes of hospitalizations of the same patients were included.Results: Serum osmolarity of NMS group was 301.83 ± 20.27 mOsm/L and control group was 294.20 ± 5.92 mOsm/L. Serum osmolarity of NMS group was statistically significantly higher than the controls (p = .018). Whole blood viscosity (WBV) at high shear rate (HSR) value of NMS group was 16.17 ± 1.48 and control group was 16.50 ± 1.38 (p = .331). Regarding WBV at low shear rate (LSR) values, also no statistically significant difference was observed between groups. LSR values of NMS and control group were 39.86 ± 30.11 and 47.41 ± 28.43, respectively (p = .387).Conclusions: Our findings indicate that serum osmolarity of NMS group was statistically significantly higher than the controls. In terms of blood viscosity, there was no statistically significant difference between groups. Higher serum osmolarity in NMS patients than controls may be a reflection of a relative hemoconcentration in NMS.KEY POINTSNMS is usually associated with dehydration resulting in fluid-electrolyte imbalance.We compared the NMS episodes with non-NMS hospitalizations (as control group) of the same patients.Serum osmolarity was statistically significantly higher in NMS group than the controls.There was no statistically significant difference between groups in terms of blood viscosity.

Does Blood Flow Change according to Mood? Blood Rheology in Bipolar Disorder.

OBJECTIVE: Bipolar disorder (BD) is associated with increased rates of cardiovascular diseases. There is growing evidence that blood viscosity may have a common role, correlated with well-known major risk factors that promote cardiovascular disease. In this study we aimed to investigate the whole blood viscosity (WBV) in different stages of BD. METHODS: A total of 121 bipolar patients and 41 age-gender matched healthy controls were included. Forty-four of bipolar patients were in manic, 35 were depressed and 42 were in euthymic state. WBV was calculated from hematocrit and total plasma protein according to Simone's formula at low and high shear rates (LSR and HSR). RESULTS: WBV at HSR of manic group was 16.91±1.01, depressive group was 17.23±0.80, euthymic group was 17.63±0.95, and control group was 17.52±0.71 (p =0.001). WBV at LSR of manic depressive, euthymic and control group were 53.10±20.58, 60.30±17.02, 8.91±20.33, and 62.01±19.28, respectively (p =0.001). Both WBV at HSR and LSR of manic group was significantly lower than that of the euthymic and control groups (p =0.001 and 0.010 respectively for HSR, p =0.001 and 0.011 respectively for LSR). WBV was significantly positively correlated with lipid profile except high density lipoprotein (HDL). CONCLUSION: Our results demonstrate a decrement in blood viscosity in manic episode compared with euthymics and controls. Positive correlation of blood viscosity with lipid parameters (except HDL), and negative correlation with number of previous manic episodes suggest that manic episode has favorable effect on cardiovascular risk regarding to blood viscosity.

Decreased circulating urokinase plasminogen activator receptor (uPAR) concentration in acute episodes of bipolar disorder; could it be a reflection of axonal injury?

INTRODUCTION: In recent years, the role of inflammation in the pathogenesis of Bipolar Disorder (BD) has been studied thoroughly. Urokinase-type plasminogen activator receptor (uPAR) is one of the molecules, whose concentration is of predictive value with regards to an ongoing inflammation and tissue regeneration, and it is hypothesized that it may also be altered in Bipolar Disorder. In this study, it is aimed to compare the levels of serum soluble uPAR during the manic, depressive and euthymic states of cases diagnosed with bipolar disorder, with healthy individuals. MATERIALS AND METHODS: Forty-four BD patients at manic state (BD-m), 35 BD patients at depressive state (BD-d), 42 euthymic patients (BD-e) and 41 healthy controls (HC) who were similar with the diseased subjects regarding age and smoking status included in the study. Serum soluble uPAR levels of patients and healthy controls were measured. RESULTS: The main finding of our study is that serum soluble uPAR levels are lower in patients diagnosed with BD either in depressive (BD-d) or in manic state (BD-m) than in BD patients in euthymic state (BD-e) or in healthy controls (HC). There was no significant difference in serum soluble uPAR concentrations between BD-m and BD-d s or between BD-e and HC with regards to serum soluble uPAR concentrations. CONCLUSIONS: Urokinase-type plasminogen (uPA) is a molecule which is an element of uPAR system and the molecules collectively take role in inflammation, tissue regeneration and axonal regeneration within the Central Nervous System (CNS). It has previously suggested in some studies that there may be a decrease in axonal density or axonal dysfunction in CNS in bipolar individuals. Accordingly, one may say that the low concentrations of soluble uPAR measured in our bipolar patients either at depressive or at manic state is due to the diminished regulatory role of soluble uPAR on axonal regeneration in CNS of BD cases.

Atherogenic index of plasma as a cardiovascular risk marker in manic, depressive, and euthymic stages of bipolar disorder.

OBJECTIVE: Individuals with bipolar disorder (BD) frequently suffer from cardiovascular disease (CVD), and it is a leading cause of mortality. Clinicians use routine laboratory tests, including a lipid profile, to predict cardiovascular risk. In addition, a particular lipid ratio, the atherogenic index of plasma (AIP), is a sensitive, new parameter that can be used to assess highrisk groups. To our knowledge, this is the first study evaluating cardiovascular risk via AIP in different stages of BD. METHODS: The study group consisted of male patients with BD who were in a manic, depressive, or euthymic state, and age- and gender-matched healthy controls. Lipid profiles were analyzed and the AIP parameter of logarithm of triglyceride (TG) / high-density lipoprotein cholesterol (HDLc) was calculated for all of the participants. The significance level was set at p<0.05. RESULTS: A total of 44 BD patients experiencing a manic episode, 35 depressive BD patients, 42 euthymic patients, and 41 healthy controls matched for age, gender, and smoking status were enrolled in the study. The AIP level was significantly different between groups (p=0.009). Pairwise comparisons of the groups revealed that the AIP level of depressive patients was significantly higher than that of the manic, euthymic, and control groups (p=0.013, p=0.048, and p=0.021, respectively). The AIP level was positively correlated with body mass index, waist circumference, metabolic syndrome, total cholesterol, low-density lipoprotein, and triglyceride level, and was negatively correlated with the HDLc level. CONCLUSION: In this study, male BD patients in a depressive episode demonstrated an increase in cardiovascular risk. The significant correlations between AIP and other conventional cardiovascular risk factors indicate that AIP may be more useful to identify individuals with BD at high risk for CVD than absolute lipid parameters.

Serum osmolarity in male patients with bipolar disorder manic episode.

NEW FINDINGS: What is the central question of this study? The main goal of this study was, for the first time, to investigate the role of the serum osmolarity in bipolar disorder manic episode. What is the main finding and its importance? Our results demonstrate a diminished serum osmolarity in manic episode compared with healthy control subjects. This finding supports the hypothesis of a fluid and electrolyte imbalance during acute episodes. Decreased serum osmolarity might be a reflection of a relative haemodilution in mania. Imbalance of water and electrolyte homeostasis has been suggested to be associated with acute episodes of bipolar disorder. In this study, we aimed to investigate, for the first time, the serum osmolarity in bipolar disorder manic episode. A total of 68 bipolar inpatients in manic episode and 60 age- and sex-matched healthy control subjects were included in the study. Serum osmolarity was calculated from sodium (Na+ ), glucose and blood urea nitrogen (BUN) according to following formula: (2 × Na+ ) + (BUN/2.8) + (glucose/18). The significance level was accepted as P < 0.05. The serum osmolarity of manic patients was 295.34 ± 4.90 mosmol/l and that of the control group was 298.46 ± 5.33 mosmol/l. The serum osmolarity of the manic group was significantly lower than that of control subjects (P < 0.001). When we compared the components of serum osmolarity, a statistically significant difference was also observed between groups in terms of glucose (85.85 ± 12.25 mg/dl for manic, 92.95 ± 20.77 mg/dl for control subjects, P = 0.019) and Na+ (140.73 ± 2.06 mmol/l for manic, 142.06 ± 2.48 mmol/l for control subjects, P = 0.001). For BUN concentrations, there was no statistically significant difference between manic (25.50 ± 9.85 mg/dl) and control (26.61 ± 6.64 mg/dl) groups (P = 0.461). Our results demonstrate a diminished serum osmolarity in manic episode compared with healthy control subjects. This finding supports the hypothesis of a fluid and electrolyte imbalance during acute episodes. Decreased serum osmolarity might be a reflection of a relative haemodilution in mania. However, exploration of the role of fluid and electrolyte homeostasis and mechanisms of related hormones may contribute to a better understanding of the aetiology of bipolar disorder.

Assessment of cardiovascular risk via atherogenic indices in patients with bipolar disorder manic episode and alterations with treatment.

OBJECTIVES: Cardiovascular disease is one of the important cause of mortality among patients with Bipolar Disorder. Castelli Risk index I and II (CRI-I and II), Atherogenic Index of Plasma (AIP) and Atherogenic coefficient (AC) are new parameters in assessing cardiovascular risk. In this study we aimed to explore the status of cardiovascular risk factors and their alterations with treatment in manic episode. METHODS: Bipolar Disorder inpatients who were in manic episode and age-gender matched healthy controls were included in the study. CRI-I, CRI-II, AIP and AC parameters were calculated before and after treatment. The statistical significance level was accepted as p<0.05. RESULTS: Sixty-eight male patients and 60 healthy controls were included in the study. CRI-I, CRI-II, AIP and AC parameters showed an increase after treatment (p<0.001 for all parameters). There was no significant difference between patients and controls in terms of CRI-I and CRI-II and AC (p=0.129, p=0.573, p=0.129 respectively). Although mean AIP levels of patients was significantly lower than control group (p=0.031), the significance disappeared when we compared the patients and controls according to being in low, medium, and high risk groups (χ2=0.826, p=0.662). CONCLUSIONS: Even in short term of treatment, antipsychotics have an important role in developing dyslipidemia and increasing cardiovascular risk. Manic state may have positive or at least no additional influences on atherogenic risk.