Neuroserpin, Tissue Plasminogen Activator, Brain-Derived Neurotrophic Factor and Interleukin-6 Serum Levels in Patients with Bipolar Disorder.

Objective To explore the association of peripheral brain-derived neurotrophic factor (BDNF) gene expression and serum protein levels with bipolar disorder (BPD). Methods The real-time quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) with TaqMan MGB was used to analyze the BDNF gene mRNA expression in peripheral leukocytes of 61 patients with BPD［32 cases with bipolar mania(BM), 29 with bipolar depression(BD)］ and 61 healthy controls. The serum BDNF level was measured with enzyme-linked immunosorbent assay (ELISA) method. The symptoms of the patients were assessed with the Hamilton Depression Rating Scale-17(HAMD17) and Young Mania Rating Scale (YMRS). Results (1) The BDNF gene mRNA expression level in BPD group (0.0077±0.0019) was significantly lower than that in control group (0.0096±0.0028) (t=-3.74, P 0.05). (2) BDNF serum levels in BPD group (2.80±0.19) was lower than that in control group (2.99±0.49) (t=-2.90, P 0.05). (3) Neither the expression levels nor serum levels of BDNF in BM were correlated with YMRS (P>0.05), and the same result was found in BD group (P>0.05). Conclusions The findings suggest that the decreased BDNF levels may be involved in the pathophysiology of BPD, while BDNF levels might not have polarized changes in different status of episodes. Key words: Bipolar disorder; Brain-derived neurotrophic factor; Gene expression

Bipolar disorder (BD) has been increasingly associated with abnormalities in neuroplasticity and cellular resilience in brain regions that are involved in mood and that affect regulation. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family that regulates neuroplasticity. The aims of the current study were to compare serum BDNF levels in euthymic adolescents with BD type I with those in controls and to investigate the relationship between clinical variables and serum BDNF levels in adolescents with BD type I. Twenty-five adolescents diagnosed with BD type I and 17 healthy control subjects within the age range of 15-19 years were recruited. Diagnoses were made by two experienced research clinicians using the Kiddie and Young Adult Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version and the affective module of Washington University in St. Louis Kiddie and Young Adult Schedule for Affective Disorders and Schizophrenia-Present State and Lifetime. Blood samples were taken during euthymia, which was defined as Young Mania Rating Scale and Hamilton Depression Rating Scale scores below 7. The comparison of BDNF serum levels between the case and healthy control groups revealed no significant differences. In the case group, BDNF levels were significantly lower in patients being currently treated with lithium. Similar to normal BDNF levels in adult patients with BD, the normal BDNF serum levels that we found in the euthymic state in adolescents and early adulthood may be related to the developmental brain stage in our study group. It may also show a common neurobiological basis of pediatric and adult BD. Further investigations evaluating BDNF levels in different mood states could help identify the role of BDNF in the underlying pathophysiology of BD.

SUBJECTIVELY AND OBJECTIVELY RATED MIXED AFFECTIVE STATES IN A MIXED-AGE SAMPLE OF ADULTS WITH BIPOLAR DISORDER: ASSOCIATIONS WITH AGE, SUICIDALITY, SYMPTOM SEVERITY, COGNITION AND INFLAMMATION

Objective: This is study aimed to determine if serum levels of brain derived neurotrophic factor (BDNF) can be used as a biological marker to make a distinction between the depressive episodes of bipolar disorder (BD) and recurrent major depressive disorder (UD). Methods: Patients between 18-65 years of age and diagnosed with BD and UD according to DSM-IV-TR diagnostic criteria, who were admitted to the outpatient clinic of psychiatry department were enrolled to the patient arm of the study. Volunteers between 18-65 years of age, who had no physical morbidity and clinical psychopathology according to DSM-IV-TR diagnostic criteria, were enrolled to the control arm of the study. There were 24 patients (11 BD and 13 UD) and 18 healthy volunteers. Patients were required to be drug naive for the past four weeks prior to the study enrollment. Hamilton Depression Rating Scale (HDRS) were applied to all patients. The serum levels of BDNF of all the subjects were studied. Results: There were no differences between groups in terms of sociodemographic variables. Total number depressive episodes were higher in BD group compared to UD group. There were no differences between BD and UD groups in terms of serum levels of BDNF. However, in patient group serum BDNF values were lower than the control group. Serum BDNF levels did not correlate with age, body mass index or gender in each group. Serum BDNF levels did not correlate with mean scores of HDRS or number of depressive episodes. Discussion: Considering the outcomes of the present study, serum BDNF levels did not demonstrate any significant difference between patient groups. However, serum BDNF levels were lower in patient groups compared to controls. For the time being there is no valid biological diagnostic marker for psychiatric disorders. The data of the present study is far from generating a biological marker for the distinction of depressive episodes of UD and BD.

We aimed to verify the impact of functional remediation (FR) on serum brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB) levels, to explore the biomechanism of FR intervention in patients with euthymic bipolar disorder (BD). This is a randomized controlled, 12-week intervention study with participants randomized into the FR group (n=39) and the treatment as usual group (TAU, n=42) at the 1∶1 ratio. 17-Hamilton Depression Rating Scale-17 (HDRS-17), Young Mania Rating Scale (YMRS), and Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) were used to assess affective symptoms and cognitive functioning both at baseline and week 12, respectively. Meanwhile, we collected blood samples (10 milliliters) from all participants for determination of serum BDNF/ TrkB levels both at baseline and week 12. After baseline assessment, all participants received FR or TAU treatments, respectively. Our results showed significant decreasing in HDRS-17 and YMRS scores, increasing in serum BDNF and TrkB levels in both groups over 12weeks (all p's<0.05). There were no group differences in the HDRS-17 and YMRS scores (all p's>0.05), but the FR group showed greater increasing in serum BDNF and TrkB levels than those in the TAU group (all p's<0.05). In terms of cognition, the change in serum BDNF levels was negatively correlated with changes in Mazes test, and the improved TrKB levels were associated with improved Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) in the FR group (all p's<0.05). The changes in serum BDNF and TrkB levels may be implicated in the mechanisms underlying FR intervention in euthymic patients with BD. A longer follow-up period than 12weeks and set up healthy controls may make the results more convincing, and the sample size of this study is still insufficient.

The aim : was to analize the prevalence of clinical types of bipolar disorder (BD) according to bipolar spectrum concept in geriatric in-patients. Study design : comparative study of the prevalence of different types of BD in aged patients with regard to the age of disease onset (before and after 60 years) in accordance with bipolar spectrum concept. Methods : all the patients included to the study were examined by psychopathological, clinical and psychometrical method (Hamilton Depression Rating Scale — HAM–D, Hamilton Anxiety Rating Scale — HARS, Young Mania Rating Scale — YMRS, MiniMental State Examination — MMSE, Montreal Cognitive Assessment — MoCA and Bipolarity Index by G. Sachs). Statistical data processing was held by STATISTICA 10.0 for Windows OS. Results : according to bipolar spectrum concept the 1st type of BD occurred in 42,7% (n = 50) examined patients, the 2nd type — in 40,2% (n = 47), the 3rd type — in 8,5% (n = 10), the 4th type — in 3,4% (n = 4), the 5th type — in 1,7% (n = 2) and the 6th type — in 3,4% (n = 4). The 1st type of BD was more often presented in patients with disease onset in young and adult age (54,0%) and in men (45,5%). The 2nd type of BD was more common for patients with disease onset in involution period (56,0%) and with late-onset BD after 60 years (50,0%), also this type more often occurred in women (46,8%). The 3rd and the 4th types were presented rarely, although, like the 1st type of BD they occurred predominantly in patients with early-onset BD (9,2 and 3,9% consequently) and in men (10,9 and 5,5% consequently). The rarest type of BD was the 5th type. The 6th type of BD was presented only in a cohort of patients with late-onset of BD (25,0%) with the same frequency in men and women. Among approximately 1/3 of examined patients the disease had its onset in the second life half (after 50 years). New onset BD occuring in the involution period (50–59 years) was more common for women, late-onset BD at the age of 60 anf older — for men. The occurrence rate of mixed affecteive states and hypomanic states increases in case of BD onset during the involution period. For late-onset BD (age 60 and older) depressive episodes with signs of transitoral cognitive disfunction were more common. Conclusion : every type of bipolar spectrum concept may occur in aged patients. New-onset BD in elderly has some special characteristics: during the involution period BD more ofter onsets in women, at the age of 60 and older — in men. Progressively as aging the frequency of new-onset BD with predominant depressive disturbances and cognitive performance disturbances increases.

Psychotherapy, Symptom Outcomes, and Role Functioning Over One Year Among Patients With Bipolar Disorder

Bipolar disorder (BD), especially BD-II, is frequently comorbid with alcohol dependence. Because BD-II and alcohol dependence are neurodegenerative disorders, agents with anti-inflammatory and neurotrophic effects might provide effective therapy. We investigated whether add-on memantine to regular valproic acid treatment ameliorated clinical symptoms, reduced alcohol use, and cytokine levels, and increased plasma brain-derived neurotrophic factor (BDNF) in BD-II patients with comorbid alcohol dependence. In a single-arm 12-week clinical trial, BD-II patients with comorbid alcohol dependence (n=45) undergoing regular valproic acid treatments were given add-on memantine (5mg/d). Symptom severity, alcohol use, cytokine (plasma tumor necrosis factor-α and C-reactive protein [CRP], transforming growth factor-β1 [TGF-β1], interleukin-8 [IL-8], IL-10), and plasma BDNF levels were regularly assessed. Mean within-group decreases in Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) scores, alcohol use, CRP, BDNF, and IL-8 levels were significantly different from baseline after 12weeks of treatment. We found no significant correlation between alcohol use levels and changes in HDRS or YMRS scores. The correlation between reduced alcohol use and reduced TGF-β1 level was significant (B=0.003, p=0.019). BD-II comorbid with alcohol dependence might benefit from add-on memantine treatment, which significantly reduced clinical severity, alcohol use, and plasma cytokine levels, and increased BDNF levels.

This study aims to investigate the effectiveness of emotion regulation training (ERT) based on Gross's process model combined with medication therapy on mania severity, depression, and emotion regulation of adults with bipolar disorder (BD) type 1. This is a randomized, controlled clinical trial on 37 adults (26 females and 11 males) with BD type 1 (depressive phase) assigned to two parallel groups of medication + ERT (n = 19) and medication (n = 18). Their mania, depression, and emotion regulation were measured by the Young mania rating scale (YMRS), the Hamilton depression rating scale (HDRS), and the emotion regulation questionnaire (ERQ) before, immediately after and 3 months after the intervention. The medication therapy included the uptake of mood stabilizers (2-5 tablets of lithium 300 mg, sodium valproate 200 mg and carbamazepine 200 mg) two times per day. The ERT was provided 2 months after receiving mood stabilizers at 8 sessions for 4 weeks, according to Gross's model. After collecting data, they were analysed in SPSS v.26 software. The difference between the two groups was statistically significant over time in the YMRS (p < 0.001, η2 = 0.42) and HDRS (p = 0.007, η2 = 0.19) scores, where more significant reductions were reported in the medication + ERT group and maintained for 3 months. Regarding the ERQ score, a significant difference between groups was observed only in the cognitive reappraisal domain (p < 0.001, η2 = 0.302) and in the total score (p = 0.001, η2 = 0.227) over time, where significant improvements were reported in the medication + ERT group and maintained for 3 months. The augmentation of medication therapy with the Gross model-based ERT can lead to a higher decrease in mania and depression and an increase in emotion regulation (cognitive reappraisal) of depressed adults with BD type 1.

To assess the frequency and severity of cognitive impairment as well as its correlations with clinical characteristics in remitted patients with bipolar disorder (BD). Eighty-five patients with BD type I (64 patients) and BD type II (21 patients) in remission were examined (average age 36.6±5.7). Affective symptoms were assessed using the Hamilton Depression Rating Scale (HDRS) and Young's Mania Rating Scale (YMRS). Cognitive impairment was assessed using the Brief Neuropsychological Cognitive Examination (BNCE). Cognitive impairment was revealed in 43.5% of the patients. The frequency and structure of cognitive impairment in patients with BD type I and type II did not differ. The patients with cognitive impairment were characterized by decreased speed of mental processes, decreased working memory and attention deficit. The correlation of the total BNCE score with the age of the patients, duration of the disease, total HDRS and YMRS scores was revealed. The results demonstrate the affective nature of cognitive deficit in the patients. Cognitive impairment in remitted patients with BD is a significant therapeutic target.

ObjectiveIn bipolar disorder, serum brain-derived neurotrophic factor (BDNF) level decreases leading to dysfunctions of critical neurotrophic, cellular plasticity and neuroprotective processes. The present study was conducted to evaluate the change in serum BDNF level with oxcarbazepine monotherapy in bipolar mania.MethodsThe present study is a prospective, interventional, open label clinical study conducted on 25 patients of bipolar mania and 25 healthy controls. Detailed history, clinical evaluation including Young Mania Rating Scale (YMRS) scoring and serum BDNF were assessed at baseline for all 50 subjects. The bipolar patients were prescribed tablet oxcarbazepine and followed up after 4 weeks for clinical evaluation and re-estimation of serum BDNF and YMRS scoring.ResultsThe serum BDNF level in bipolar manic patients were compared with healthy controls at baseline and results revealed that there is a significant reduction (p=0.002) in serum BDNF level in bipolar patients. At follow-up after 4 weeks, the mean change in serum BDNF in bipolar group who were on oxcarbazepine monotherapy was found statistically significant (p=0.02) in comparison to healthy controls. In bipolar group, the YMRS score and serum BDNF at baseline have an inverse relation(r=−0.59) whereas change of the YMRS score had a positive correlation (r=0.67) with the change of serum BDNF over 4 weeks.ConclusionIn bipolar mania serum BDNF level is low and it is found to be increased with short term monotherapy with oxcarbazepine.

Early identification of patients with bipolar disorder during their first depressive episode is beneficial to the outcome of the disorder and treatment, but traditionally this has been a great challenge to clinicians. Recently, brain-derived neurotrophic factor (BDNF) has been suggested to be involved in the pathophysiology of bipolar disorder and major depressive disorder (MDD), but it is not clear whether BDNF levels can be used to predict bipolar disorder among patients in their first major depressive episode. To explore whether BDNF levels can differentiate between MDD and bipolar disorder in the first depressive episode. A total of 203 patients with a first major depressive episode as well as 167 healthy controls were recruited. After 3 years of bi-annual follow-up, 164 patients with a major depressive episode completed the study, and of these, 21 were identified as having bipolar disorder and 143 patients were diagnosed as having MDD. BDNF gene expression and plasma levels at baseline were compared among the bipolar disorder, MDD and healthy control groups. Logistic regression and decision tree methods were applied to determine the best model for predicting bipolar disorder at the first depressive episode. At baseline, patients in the bipolar disorder and MDD groups showed lower BDNF mRNA levels (P<0.001 and P = 0.02 respectively) and plasma levels (P = 0.002 and P = 0.01 respectively) compared with healthy controls. Similarly, BDNF levels in the bipolar disorder group were lower than those in the MDD group. These results showed that the best model for predicting bipolar disorder during a first depressive episode was a combination of BDNF mRNA levels with plasma BDNF levels (receiver operating characteristics (ROC) = 0.80, logistic regression; ROC = 0.84, decision tree). Our findings suggest that BDNF levels may serve as a potential differential diagnostic biomarker for bipolar disorder in a patient's first depressive episode.

Decreased Brain-Derived Neurotrophic Factor in Older Adults with Bipolar Disorder

Bipolar disorder (BD) is a prevalent, chronic and progressive illness. There is a growing body of evidence indicating that brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of BD. The aim of this study was to evaluate BDNF plasma levels in BD patients with long term illness in comparison with controls. 87 BD type I patients and 58 controls matched by age, gender and education level were enrolled in this study. All subjects were assessed by the Mini-International Neuropsychiatric Interview and the patients by the Young Mania Rating Scale and the Hamilton Depression Rating Scale. The plasma levels of BDNF were measured by ELISA. On average, patients had suffered from BD for 23.4 years. In comparison with controls, BD patients with mania presented a 1.90-fold increase in BDNF plasma levels (p = .001), while BD patients in remission presented a 1.64-fold increase in BDNF plasma levels (p = .03). BDNF plasma levels were not influenced by age, length of illness or current medications. The present study suggests that long-term BD patients exhibit increased circulating levels of BDNF.

To comparatively evaluate the efficacy and safety of the two aripiprazole long-acting injectable (LAI) initiation regimens, including one-injection start (OIS) regimen and two-injection start (TIS) regimen, in patients with bipolar disorder (BD). A total of 46 BD patients experiencing acute manic episodes with psychotic or mixed features were included in this observational study. Patients were divided into two groups based on the aripiprazole LAI initiation regimen including OIS group (n=23; patients received a single 400 mg LAI injection on Day 1, followed by oral aripiprazole (15-20 mg/day) for 14 days) and TIS group (n=23; patients received two 400 mg doses of aripiprazole LAI administered on the same day together with a single 20 mg oral dose of aripiprazole). Data on patient demographics, clinical characteristics and previous hospitalization were retrieved from hospital records. The effectiveness of the treatment was evaluated based on the Young Mania Rating Scale (YMRS) and Hamilton Depression Scale (HAM-D) scores recorded on Day 1 and Day 15 of the injection. The safety and tolerability of the OIS and TIS regimens were assessed via Udvalg for Kliniske Undersøgelser Side Effect Rating Scale (UKU-SERS) scores recorded on Day 15 of the injection. At baseline, the rate of previous hospitalization was higher in the OIS group than in the TIS group (60.9% vs. 26.1%, p=0.037). YMRS scores on Day 15 (11.0 ± 5.7 vs. 16.6 ± 6.2, p=0.003) and UKU-SERS Psychiatric adverse effects score on Day 15 (4.4 ± 1.8 vs. 7.5 ± 3.2, p<0.001) were significantly lower in the TIS group than in the OIS group. YMRS scores and HAM-D scores were significantly decreased from Day 1 to Day 15 of injection in both TIS (p= 0.002 and p=0.025, respectively) and OIS (p= 0.002 and p=0.025, respectively) groups, while the change was significantly higher in the TIS group. Linear regression analysis revealed that OIS regimen was a significant risk factor for increase in YMRS Day 15 scores (B: 0.434, p=0.003) and increase in UKU-SERS psychiatric scores (B: 0.526, p<0.001). Logistic regression analysis revealed that OIS regimen was an independent determinant of previous hospitalization history (OR: 4.407, p=0.020), increasing the likelihood of previous hospitalization by 4.407 times compared to TIS regimen. Both regimens had tolerable side effects, with no life-threatening issues. This study highlights the efficacy and reliability of the TIS regimen in treating BD episodes, potentially facilitating faster clinical recovery by reducing the need for prolonged oral supplementation.