High Mobility Group Box 1 Levels as an Inflammatory Mediator in Bipolar Mania.

Introduction: High mobility group box 1 protein (HMGB1) is a member of the molecular family known as damage-associated molecular patterns, which is implicated to have a role in neuroinflammation processes. In recent years, a growing number of studies have focused on the role of inflammation in Bipolar Disorder (BD). This study aimed to investigate the serum levels of HMGB1 and other inflammatory markers in patients with bipolar manic episodes compared to those in healthy controls (HC). Methods: A single-center, observational, case-control study was conducted. Thirty-five patients with BD in manic episodes and 35 HC were assessed. Young Mania Rating Scale (YMRS) was used to assess the symptom severity of the patient group. While inflammatory markers (such as HMGB1, C-reactive protein (CRP) and white blood cell count) were assessed at the first three and the last day of hospitalization in the patient group, they were evaluated once in HC. Levels of inflammatory markers were compared between (patient-HC) and within groups (before-after treatment). Results: No difference was observed in serum HMGB1 levels of bipolar patients with manic episodes compared to the HC (p>0.05). C-reactive protein levels of manic patients were higher than HC (p<0.001), and the difference persisted even after treatment (p=0.007). In addition, there was a significant positive correlation between CRP levels and antipsychotic drug dosage (r=0.382, p=0.024). Conclusion: There were no differences in HMGB1 levels between bipolar patients with acute manic episode and HC. However, higher CRP levels in bipolar patients support the low-grade inflammation hypothesis in the etiology of BD.

Eveningness chronotype influences social functioning by deteriorating depressive symptoms in remitted patients with schizophrenia.

Sleep and circadian rhythm disruption (SCRD) is common in schizophrenia patients, who also typically experience impaired social functioning. While various factors influence social functioning in schizophrenia, the specific impact of sleep and circadian rhythm disruption remains unclear. This study aimed to investigate the connection between chronotype and social functioning in remitted schizophrenia patients, examining the mediating roles of depression and sleep quality. The study included 185 patients diagnosed with schizophrenia based on DSM-5 criteria. After categorizing the patients into morningness, eveningness, or intermediate chronotypes using the Morningness-Eveningness Questionnaire(MEQ), they were assessed with the Positive and Negative Syndrome Scale(PANSS), Calgary Depression Scale for Schizophrenia(CDSS), Personal and Social Performance Scale(PSPS) and Pittsburgh Sleep Quality Index(PSQI). The eveningness chronotype group showed higher CDSS and PSQI scores and lower PWBS and PSPS-Total scores than the other groups (p < 0.05). A hierarchical linear regression model assessed MEQ, PSQI, and CDSS scores' effects on PSPS total scores. MEQ scores' significance diminished when CDSS scores were included. Eveningness chronotype, particularly with increased depressive symptoms, negatively impacts social functioning in remitted schizophrenia patients.These findings contribute to the understudied area of chronotype in schizophrenia and its impact on social functioning, including its interaction with sleep..

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.

The emotions experienced by family medicine residents and interns during their clinical trainings: a qualitative study.

BACKGROUND: The family medicine residents and final year medical students are challenged with increased workload and they experience various emotions during their clinical trainings. They are confronted with uncertainties in their role descriptions and they witness illness, suffering and deaths as part of their everyday duties which may lead to burnout. Only several studies have focused on these experiences to find out what the family medicine residents and medical students were literally feeling. AIM: The aim of this study was to explore the family medicine residents' and final year medical students' emotions during their clinical trainings. METHOD: This qualitative study was performed with 15 family medicine residents and 24 final-year medical students using a convenience sample from two medical faculties to explore and analyze their emotions. Data were gathered by means of focus group interviews, including six interviews conducted and recorded through online meetings. Data were analyzed for themes using a thematic analysis approach. Since the interviews reached saturation in terms of content, the interviews were terminated at the end of sixth focus group meetings. Each interview took an average of 45-60 min. RESULTS: Three main themes emerged from the data regarding residents' and interns' emotions. These were the "clinical climate's role", "emotions during patient encounters" and "coping strategies with negative emotions". The most commonly encountered emotions were tension and anxiety followed by frustration and uncertainty. CONCLUSIONS: The family medicine residents and final-year medical students are challenged with emotions during their clinical trainings. Therefore, medical educators have to be aware of the need to support them in reflecting their emotions by prioritizing residents'and interns' well-being.

Ten-Year Follow-Up of Earthquake Survivors: Long-Term Study on the Course of PTSD Following a Natural Disaster.

Objective: Few earthquake survivor studies extend follow-up beyond 2 years, leaving the long-term course of earthquake-related posttraumatic stress disorder (PTSD) unknown. This 10-year survey re-assessed the 1999 Izmit, Turkey, earthquake survivors.Methods: Izmit earthquake survivors (N = 198), previously assessed for PTSD/partial PTSD at 1-3 months and 18-20 months post-earthquake, were evaluated 10 years post-event from January 2009 through December 2010. A PTSD self-test (Turkish translation) used DSM-IV criteria to characterize full PTSD, "stringent partial PTSD," "lenient partial PTSD," or non-PTSD based on symptom type/amount.Results: Full PTSD prevalence decreased from 37% at 1-3 months post-earthquake to 15% at 18-20 months (P < .001), remaining relatively stable (12%) at 10 years (P = .38). Stringent and lenient partial PTSD decreased between 1-3 months and 18-20 months (from 9% to 3% and from 24% to 12%, respectively; P < .001), remaining stable at 10 years (5% and 9%, respectively; P = .43 and P = .89). PTSD was more prevalent at 1-3 months among those who had a close acquaintance harmed, had been evacuated for long periods (> 1 week), or had more children; this was not observed at 10 years (P = .007-.017). Avoidance symptoms 1-3 months post-earthquake were the best predictor for full PTSD at 10 years (P < .001). Delayed-onset PTSD was observed in only 2% of participants.Conclusions: Full and partial PTSD decreased over the first 2 years post-trauma, but remained stable at 10 years, suggesting PTSD symptoms at around 2 years remain stable at 10 years. Background characteristics did not predict PTSD long-term course, but avoidance level did. Delayed-onset PTSD was relatively rare.

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.

Can optical coherence tomography findings be related with suicide attempt in bipolar disorder?

BACKGROUND: The aim was to investigate the relationship between OCT findings and suicidal behavior (SB) in patients with Bipolar Disorder type 1 (BPD1) in comparison to healthy controls. METHODS: Forty five euthymic BPD1 patients with previous suicide attempts (BPD1+), 46 euthymic BPD1 patients without previous suicide attempts (BPD1-) and 63 healthy controls were included. The subjects were evaluated with Sociodemographic Data Form, SCID, Suicide Behaviors Questionnaire, Beck Depression Inventory, Young Mania Rating Scale and OCT. RESULTS: All OCT measures were lower in patients with BPD1 than healthy controls (p<0.001). While no significant differences were found between (BPD1+) and (BPD1-) in all GCC levels and inferior RNFL values (p>0.05), the superior RNFL and global RNFL values were found to be lower in the (BPD1+) than in the (BPD1-) (p = 0.037, p = 0.028, respectively). Global RNFL was found to significantly predict suicide risk in a multivariate logistic regression model (p = 0.024 Exp(B):0.930). CONCLUSIONS: Neurodegeneration might occur during the course of BPD1 and SB. Decreased RNFL may be important for neurodegeneration related to SB.

Can the Imbalance between Neurotrophic and Apoptotic Proteins Be the "Beware the Ides of March" for Unaffected Relatives of Schizophrenia Patients?

Schizophrenia (SZ) is a mental disorder with a strong genetic basis as well as epigenetic aspects. Siblings of patients with SZ can share certain endophenotypes with the patients, suggesting that siblings may be important for distinguishing between trait and state markers. In the current study, we aimed to characterize the balance between pro-BDNF/mature BDNF and its receptors p75NTR/TrkB, which are tPA-BDNF pathways proteins and are thought to play a role in synaptic pruning, as a possible endophenotype of schizophrenia. Forty drug-naïve patients with first-episode psychosis (FEP) matched for age, gender, and level of education, 40 unaffected siblings (UAS) of patients with FEP, and 67 healthy controls (HC) were included in the study. Blood samples were collected from all participants to determine BDNF, pro-BDNF, TrkB and p75NTR, PAI1, tPA, ACTH, and cortisol levels. We showed that levels of proteins of the tPA-BDNF pathway as well as the pro-BDNF/m-BDNF and p75NTR/TrkB ratios could successfully differentiate FEP and their siblings from the HCs by using ROC analysis. Plasma levels of m-BDNF were found to be the lowest in the healthy siblings and highest in the HCs with statistically significant differences between all 3 groups. The plasma level of pro-BDNF in the HC group was similar to the FEP patients, the same in the healthy siblings of the FEP patients. Our data support the hypothesis that imbalance between neurotrophic and apoptotic proteins might occur in SZ and this imbalance could be an endophenotype of the disease.

Serum nitric oxide levels are depleted in depressed patients treated with electroconvulsive therapy.

BACKGROUND: Nitric oxide (NO) is an endogenous substance which has several endocrine functions and may act as neurotransmitter in the brain. High levels of NO may provoke nitrosative stress. AIM: It was aimed to examine serum levels of NO in patients with depressive episodes who were treated with electroconvulsive therapy (ECT) in this study. METHODS: The design was a case-control, follow-up study. Patients with depressive episodes (n = 23) and a healthy control group (n = 21) were enrolled. Three serum samples were obtained from the patient group (before ECT, after first and seventh sessions). NO, nitrite, and nitrate levels were examined. STATISTICAL ANALYSIS: Differences between groups were examined with t-test or Mann-Whitney U-test. Longitudinal data were evaluated with Panel Regression Analysis and Kruskal-Wallis Test. RESULTS: Serum levels of NO and nitrite decreased significantly after the seventh session of ECT administration compared to the baseline and first session. Nitrate levels did not differ between the assessments. CONCLUSIONS: Reduction of the serum NO and nitrite levels might be a contributing factor for hypertension during the sessions. These findings are reflect the circulating NO levels. Further studies may dissect NO physiology in the brain in mental disorders and potential external effects.

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.

A novel commentary: Investigation of the role of a balance between neurotrophic and apoptotic proteins in the pathogenesis of psychosis via the tPA-BDNF pathway.

OBJECTIVE: Many hypotheses have put forward to better understand the pathogenesis of schizophrenia (SZ), such as synaptic pruning, stress-diathesis, neurodevelopment, neurodegeneration and neurotransmitter hypothesis; nonetheless, this pathogenesis still remains a mystery. The current study was designed with the hypothesis that impairment of a balance between pro-BDNF/mature BDNF and their receptors p75NTRK/TrkB may cause synaptic pruning in the pathogenesis of psychotic disorders. METHODS: Sixty-five drug-naïve patients with first-episode psychosis (FEP) who applied to outpatient clinics and were diagnosed according to DSM-5 as well as 65 healthy controls (HC) were included in the study. Symptoms at the time of evaluation were assessed with the PANSS scale by an experienced psychiatrist. Blood samples were collected from all participants to determine BDNF, pro-BDNF, TrkB and p75NTR, PAI1, tPA, ACTH and cortisol levels. RESULTS: Mature BDNF, TrkB and PAI-1, tPA levels were significantly lower while the levels of ACTH and cortisol were significantly higher in FEP patients compared to HC. No significant difference was found in pro-BDNF and p75NTR levels between the two independent groups. The pro-BDNF/mature BDNF and the p75NTR/TrkB ratios were significantly higher in FEP patients compared to HC. Moreover, the pro-BDNF/mature BDNF and the p75NTR/TrkB ratios were found to be significantly associated with the pathogenesis of SZ in a hierarchical regression model. DISCUSSION: Imbalance between neurotrophic and apoptotic proteins such as pro-BDNF/mature BDNF and p75NTR/TrkB may be take part pathogenesis of synaptic pruning in psychotic disorders.

Electroconvulsive Therapy and Extracellular Matrix Glycoproteins in Patients with Depressive Episodes.

Background: The brain extracellular matrix (ECM) is composed of glycoproteins deriving from the cell membrane and joining into nets called perineuronal nets (PNNs). The ECM glycoproteins limit neuroplasticity, cell proliferation, and differentiation. Electroconvulsive therapy (ECT) is provided by electrical currents that may alter several cascades and biophysical effects. ECM conformation might be influenced by the effects of ECT. Methods: Patients with depressive disorders (n = 23) and healthy control subjects (n = 21) were enrolled. Serum levels of the ECM glycoproteins versican, brevican, neurocan, phosphocan and tenascin C were measured with enzyme-linked immunosorbent assay. Serum samples were collected from the patients in the patient group at 3 time points: before ECT, 30 min after the first session, and 30 min after the seventh session. Results: There was a significant difference in tenascin C levels (P = .001) between the groups. No other significant difference was observed. Serum levels of the measured ECM glycoproteins and prolidase activity did not differ in the depression group after the administration of ECT. Conclusions: Our results did not support the claim suggesting a possible mechanism for modulation of ECM glycoproteins by ECT. Serum levels may not necessarily reflect conformational changes in the ECM. Further studies are needed to investigate the effects of ECT on ECM glycoproteins. Modulation of the ECM may provide a new window suggesting improvement in treatments.

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.