Evaluation of the Process of Acute Treatment for Depression in Terms of Monitoring Activity and Sleep Efficiency with Actigraphy.

Background: This study aimed to evaluate and follow-up the process of acute treatment for depression in terms of activity and sleep efficiency using actigraphy, and thus increase the opportunities for objective measurement in the monitoring of treatment. Methods: A total of 20 patients with depression, and 22 and age- and gender-matched healthy volunteers were included in the study. All subjects were evaluated using a sociodemographic data form, the Hamilton Depression Rating Scale (HDRS), and actigraphy for measurement of motor activity and sleep efficiency. Results: The activity levels and sleep efficiency of the controls were significantly higher than the pre-and post-treatment activity levels and sleep efficiency of the patients. After the treatment process, both motor activity and sleep efficiency were found to be significantly increased in the patients. A highly significant negative correlation was found between the HDRS scores and average activity counts for active intervals (r = -0.779, P < .001), and between the HDRS scores and sleep efficiency (r = -0.616, P < .001). On the other hand, a significant negative effect was found between depression and average activity counts for active intervals (RR:0.880; 95% CI:0.782-0.991). Conclusions: Actigraphy is a useful technique for quantifying physical activities and sleep efficiency in depressed patients. Furthermore, it may provide objective follow-up data in assessing the effects of treatment for depression.

Minor Physical Anomalies in Bipolar Disorder.

OBJECTIVE: High-arched palate is more frequent in schizophrenia and bipolar disorder (BD). Upto 40% of patients develop schizophrenia in 22q11.2 Deletion Syndrome manifested with cleft lip and palate, which originate from the first pharyngeal arch in embryo. The auricle also originates from the dorsal ends of the first and second pharyngeal arches; hence, we aimed to determine the associations between auricular anomalies and BD. METHODS: We screened for 36 minor physical anomalies of the auricle in 146 patients with BD. RESULTS: 7 out of the of 36 assessed anomalies highly differed between healthy subjects and BD patients. A regression model including the differing anomalies predicted healthy subjects and BD-patients by 78.8% and 68.5%, respectively. CONCLUSIONS: Assessing minor anomalies in psychiatric disorders may help to discover novel pathogenesis pathways and even new endophenotypes.

Evaluation of 2D:4D digit ratio in bipolar 1 disorder patients and its relationship with treatment response.

BACKGROUND: The role of sex steroids in bipolar disorder (BD) has been demonstrated in adults. We aimed to evaluate the 2D:4D ratio, which indirectly reflects prenatal sex steroids, in BD. Another purpose of this study was to determine the relationship between clinical features, especially lithium response, and digit ratio. METHODS: The study included 74 patients with bipolar 1 disorder and 74 healthy individuals matched according to age, gender, and educational status. The digit ratio was calculated by dividing the index finger (2D) length by the ring finger (4D) length in both hands. A lithium response scale was used to evaluate the lithium response history. RESULTS: There was no difference in 2D:4D ratio between the patients and controls in either right or left hands. The digit ratio was not different between groups with and without suicide attempts. The 2D:4D ratio in the patient group was lower in individuals unresponsive to lithium therapy than in partial and good responders for both right and left hands. DISCUSSION: According to the results of our study, the 2D:4D ratio in the BD group was not different from healthy controls but was lower in patients unresponsive to lithium. In this respect, the 2D:4D ratio can be considered as a biomarker for lithium response in BD. In large-sample studies, the 2D:4D ratio should be investigated for pathophysiology and treatment response of BD.

[Ten-Year Risk of Cardiovascular Disease in Patients with Bipolar Disorder]. / Bipolar Bozukluk Tanili Hastalarda 10 Yillik Kardiyovasküler Hastalik Riski.

OBJECTIVE: Patients with bipolar disorder (BPD) are less likely to seek treatment for cardiovascular diseases (CVD) despite the two fold increased CVD-related death rate in BPD. The aim of this study was to evaluate the relationship between clinical variables, exercise characteristics and 10-year risk of CVD in patients with bipolar I disorder (BPD-I). METHOD: The study was carried out with 106 euthymic BPD-I patients who were followed up at the Mood Disorders Centers of Bakirköy Hospital for Mental and Neurological Diseases and Selcuk University Faculty of Medicine. The physical activity status of the patients were evaluated with the Godin Leisure-Time Exercise Questionnaire (GLTEQ) and the prospective 10-year risk of CVD was assessed by the QRISK®2-2017 - CVD risk algorithm. RESULTS: Mean age of the patients were 39.5±8.6 years. The mean QRISK2 score of the patients was 3.64±0.46 %, which did not differ with respect to the gender. Patients' mean healthy heart age (QAGE) was 8.49±6.46 years ahead of their current age. There was a weak negative correlation between GLTEQ total score and QRISK2 score (r= 0.168), but this was not statistically significant. However, statistically significant positive correlations were determined between the categorical QRISK2 score and the disease age of onset (RR:1.18; 95%CI:1.09-1.28), treatment duration (RR:1.16; 95%CI:1.05-1.29) and the inclusion of atypical antipsychotic agents in the treatment received (RR:5.99; 95%CI:1.12-31.90). CONCLUSION: A strong positive correlation was determined in this study between the QRISK2 score and the use of atypical antipsychotic drugs in the treatment of the BPD-I patients. It is important to identify patients diagnosed with bipolar disorder with a high risk of developing CVD to review the psychiatric treatment and to encourage the patients for preventive approaches.

Involvement of hemoglobins in the pathophysiology of Alzheimer's disease.

Hemoglobins (Hbs) are heme-containing proteins binding oxygen, carbon monoxide, and nitric oxide. While erythrocytes are the most well-known location of Hbs, Hbs also exist in neurons, glia and oligodendroglia and they are primarily localized in the inner mitochondrial membrane of neurons with likely roles in cellular respiration and buffering protons. Recently, studies have suggested links between hypoxia and neurodegenerative disorders such as Alzheimer Disease (AD) and furthermore suggested involvement of Hbs in the pathogenesis of AD. While cellular immunohistochemical studies on AD brains have observed reduced levels of Hb in the cytoplasm of pre-tangle and tangle-bearing neurons, other studies on homogenates of AD brain samples observed increased Hb levels. This potential discrepancy may result from differential presence and function of intracellular versus extracellular Hbs. Intracellular Hbs may protect neurons against hypoxia and hyperoxia. On the other hand, extracellular free Hb and its degradation products may trigger inflammatory immune and oxidative reactions against neural macromolecules and/or damage the blood-brain barrier. Therefore, biological processes leading to reduction of Hb transcription (including clinically silent Hb mutations) may influence intra-erythrocytic and neural Hbs, and reduce the transport of oxygen, carbon monoxide and nitric oxide which may be involved in the (patho)physiology of neurodegenerative disorders such as AD. Agents such as erythropoietin, which stimulate both erythropoiesis, reduce eryptosis and induce intracellular neural Hbs may exert multiple beneficial effects on the onset and course of AD. Thus, evidence accumulates for a role of Hbs in the central nervous system while Hbs deserve more attention as possible candidate molecules involved in AD.

Affective Temperament and Seasonality in Bipolar Disorder.

BACKGROUND: Both affective temperaments and seasonality impact on the illness course in bipolar disorder (BD). This exploratory study aims to investigate the link between seasonality and affective temperament in BD. SUBJECTS AND METHODS: Sixty-six euthymic patients with BD-I were recruited. The Seasonal Pattern Assessment Questionnaire (SPAQ) and Temperament Evaluation Memphis, Pisa, Paris and San Diego-Autoquestionnaire version scale (TEMPS-A) were applied. RESULTS: The seasonal BD rate was 39.4% (n=26). Depressive and anxious temperament scores were higher in patients with seasonality. The SPAQ total scores were also associated with depressive, cyclothymic, and anxious affective temperament scores. CONCLUSION: Our findings warrant further investigation to understanding the complex interaction between seasonality, mood regulation, and temperament collectively moderating illness course in BD. This study implies that affective temperament may have some value in discerning the link between seasonality and illness course in BD.

Reliability and Validity Study of the Turkish Version of Bipolar Spectrum Diagnostic Scale. / Bipolar Spektrumu Tani Ölçegi Türkçe Formu’nun Güvenilirlik ve Geçerlilik Çalismasi.

OBJECTIVE: The purpose of this study is to evaluate the reliability and validity of the Turkish Version of the Bipolar Spectrum Diagnostic Scale (BSDS). METHOD: The study was carried out with 130 patients diagnosed with bipolar I disorder, 15 patients diagnosed with bipolar II disorder, and 38 patients diagnosed with major depressive disorder attending the outpatient psychiatry departments of the Bakirköy Prof. Dr. Mazhar Osman Training and Research Hospital for Mental Health and Neurological Diseases. The Mood Disorder Questionnaire (MDQ) was used for convergent validity. The internal consistency coefficient, itemtotal score correlation coefficients, test-retest correlation coefficient, confirmatory factor analysis, correlation with concurrent scale, and ROC curve were statistically calculated. RESULTS: Confirmatory factor analysis indicated that the 20-item version did not show adequate goodness-of-fit. The item 4 with a relatively low regression weight was removed from the model. For the 19-item revised and corrected model, the observed goodness-of-fit indexes were RMSEA = 0.040, CFI = 0.900, GFI = 0.890, IFI = 0.900 and χ2/df = 1.230. The internal consistency Cronbach's alpha coefficient was 0.831. The correlation coefficient between the Turkish version of the BSDS and the MDQ was 0.54. The cutoff point of the scale calculated by the ROC analysis was 12 with a sensitivity of 78.6% and a specificity of 86.8%. CONCLUSION: The Turkish Version of the BSDS, has been shown to be reliable and valid tool for screening bipolar disorder after removal of the item 4 of the original version of the scale.

[Evaluation of the Association between Lithium Treatment and GSK3ß Polymorphism in Bipolar Disorder Patients]. / Iki Uçlu Bozukluk Hastalarinda Lityuma Yanit ile GSK-3ß Polimorfizmi Iliskisinin Degerlendirilmesi.

OBJECTIVE: There is a lack of evidence regarding clinical predictors for the treatment response to lithium, which is the main stay treatment option for bipolar disorder. Studies that examined the mechanistic action of lithium revealed that glycogen synthase kinase 3ß (GSK-3ß) enzymeinhibition was important in regard to treatment responses. Based on this background, we aimed to investigate the association between responses to lithium treatment and five different polymorphisms of GSK-3ß. METHOD: Lithium treatment response scale (LTRS) scores for 100 patients diagnosed with bipolar disorders type I were calculated according to the hospital records. Blood samples were collected and genomic DNA was obtained using the MagNA Pure Compact automatic isolation method. The GSK-3ß: rs17183904, rs17183897, rs34009575, rs34002644, and rs17183890 polymorphisms were analyzed by real time PCR. RESULTS: In this cohort, the mean age of patients was 41.1±10.3 years, the mean age of disease onset was 24.5±8.2, and the mean LTRS score was 4.9±1.8. There was no statistically significant difference for LTRS scores between groups in terms of gender, marital status, level of education, and the type of first episode. LTRS was significantly higher in only the patients harbouring GSK-3ß rs17183890 AG genotype (p=0.008, t:2.71). Interestingly, no differences were found for the remaining polymorphisms. CONCLUSION: The specific GSK-3ß polymorphism that associated with lithium-response in our study may help to predict lithium responses and to develop individualized treatment. We presume that our pharmacogenomic findings may also provide important contributions to the clinical practice in regard to future evaluation of the treatment adherence and side effects. To obtain these goals, further genome-wide scanning studies conducted on larger sample cohorts are required.

Hemoglobins emerging roles in mental disorders. Metabolical, genetical and immunological aspects.

Hemoglobin (Hb) expression in the central nervous system is recently shown. Cooccurences of mental disorders (mainly bipolar disorder (BD) and tic disorders) with ß- or α-thalassemia trait or erythrocytosis were witnessed, which may be due to peripheral or central hypoxia/hyperoxia or haplotypal gene interactions. ß-Globin genes reside at 11p15.5 close to tyrosine hydroxylase, dopamine receptor DRD4 and Brain Derived Neurotrophic Factor, which involve in psychiatric diseases. α-Globin genes reside at 16p13.3 which associates with BD, tic disorders, ATR-16 Syndrome and Rubinstein Taybi Syndrome (RTS). CREB-Binding Protein (CEBBP)-gene is mutated in RTS, which commonly associates with mood disorders. 16p13.3 region also contains GRIN2A gene encoding N-methyl-d-aspartate receptor-2A and SSTR5 (Somatostatin Receptor-5), again involving in mental disorders. We demonstrated a protective role of minor HbA2 against post-partum episodes in BD and association of higher minor HbF (fetal hemoglobin) levels with family history of psychosis in a BD-patient cohort. HbA2 increases in cardiac ischemia and in mountain dwellers indicating its likely protection against ischemia/hypoxia. HMGIY, a repressive transcription factor of δ-globin chain of HbA2 is increased in lymphocytes of schizophrenics. In autism, deletional mutations were found in BCL11A gene, which cause persistence of HbF at high levels in adulthood. Also, certain polymorphisms in BCL11A strongly associate with schizophrenia. Further, many drugs from anabolic steroids to antimalarial agents elevate HbF and may cause mania. We ascribe a protective role to HbA2 and a maladaptive detrimental role to HbF in psychopathology. We believe that future studies on hemoglobins may pave to discover novel pathogenesis mechanisms in mental disorders.

Higher minor hemoglobin A2 levels in multiple sclerosis patients correlate with lesser disease severity.

OBJECTIVE: To define whether minor adult hemoglobin A2 (HbA2, α2δ2) exerts any protective activity in multiple sclerosis (MS). METHODS: HbA2 levels were measured in 146 MS patients with high performance liquid chromatography and association with MS Severity Scores (MSSS) were determined. HbA2 associations with blood count parameters were also studied using blood counts evaluated on the same day of high performance liquid chromatography sampling. Routine biochemical parameters were also determined to rule out elusively influential factors, such as anemia and thyroid disorders. RESULTS: HbA2 levels negatively correlated with MSSS (Spearman correlation, R: -0.186, P=0.025). Exclusion of confounding factors with a generalized linear model revealed an even stronger negative correlation between HbA2 and MSSS (P<0.001). HbA2 positively correlated with red blood cells (RBCs) (R=0.350, P<0.001) and in turn, RBCs negatively correlated with MSSS (R=-0.180, P=0.031). Average HbA2 levels were highest among patients treated with interferon ß1a. CONCLUSION: RBC fragility is increased in MS, and recent data suggest that circulating free Hb contributes to neural injury in MS. HbA2 and its oxidative denaturation product hemichrome A2 enhance RBC membrane stability to a greater extent than do major HbA or hemichrome A. Reductions in ischemic cerebrovascular vascular events are reported in ß-thalassemia carriers and HbA2 levels are considerably higher in this population. Episodic declines of cerebral blood flow were shown in bipolar disorder, and we have recently shown a protective role of HbA2 against postpartum episodes in females with bipolar disorder. HbA2's erythroprotective functions may reduce free Hb and long-term neural injury in MS.

Hemoglobins as new players in multiple sclerosis: metabolic and immune aspects.

Basic science investigations and clinical observations in recent years indicate that hemoglobins (Hbs) may have important roles in the pathogenesis of multiple sclerosis (MS). These findings can be summarized as follows: 1- Erythrocyte fragility is higher in MS patients, the released free Hb damages blood-brain barrier, myelin basic protein and also triggers iron overload and inflammation. 2- Free Hb may further activate the inflammatory responses through Toll-like receptor 4 (TLR4), present on microglia and other innate immunocytes. 3- Hbs are expressed in neural cells including dopaminergic neurons. Also, several studies have demonstrated that Hbs are expressed in astrocytes and oligodendroglia. 4- Hb overexpression in neural cells upregulate mitochondrial complex I-V subunits. The comparison of the mitochondrial proteome between healthy and patients with MS revealed only four differentially expressed proteins including Hb ß-chain. 5- Microarray analysis of 8300 genes in monocytes of twins with and without MS showed a difference in 25 genes that include genes encoding α- and ß-globins as well. 6- ß- and α-globin gene clusters reside at chromosomal regions 11p15.5 and 16p13.3, respectively. Whole genome screen (WGS) in Sardinian MS families using 327 markers revealed linkage in 3 regions including 11p15.5 loci. Further, 11p15.5 and 16p13.3 were part of the 17 regions identified in the WGS study of 136 sibling-pairs in Nordic countries analyzing 399 microsatellite markers. In the light of these findings, we propose that free Hb released from dying erythrocytes is detrimental. On the contrary, intracellular Hbs in neural cells are protective in MS. The genomic linkage findings can be explained by common haematologically-silent Hb variants that may lower the protective function of intracellular Hbs, and therefore, enhance the risk for MS. In the absence of such variants, aberrations in the translational and post-translational mechanisms controlling synthesis of neural Hbs may also enhance the vulnerability to MS. Alternatively, such genetic variants may perturb the metabolism of anti-inflammatory hemorphins produced via cleavage of Hbs.

Hemoglobins, Hemorphins, and 11p15.5 Chromosomal Region in Cancer Biology and Immunity with Special Emphasis for Brain Tumors.

In systemic cancers, increased hemolysis leads to extracellular hemoglobin (HB), and experimental studies have shown its provoking role on tumor growth and metastasis. However, investigations have shown that HB chains presented by tumor vascular pericytes or serum protein complexes of HB could also induce antitumor immunity, which may be harnessed to treat refractory cancers and brain tumors. Mounting recent evidence shows that expression of HBs is not restricted to erythrocytes and that HBs exist in the cells of lung and kidney, in macrophages, and in neurons and glia of the central nervous system (CNS). HBs mediate coping with hypoxia and free radical stress in normal and tumor cells, and they are increased in certain tumors including breast, lung, colon, and squamous cell cancers. Recent studies showed HBs in meningioma, in the cyst fluid of craniopharyngioma, in the cerebrospinal fluid (CSF) of pediatric patients with posterior fossa tumors, and in glioblastoma cell lines. Hemorphins, abundant brain peptides formed via HB-chain cleavage, exert opioid activity and antiproliferative and immunomodifier effects. Hence mutations in HBs may modify brain tumorigenesis via influencing hemorphins and perturbing regulations of immune surveillance and cell growth in the neuroectodermal tissues. The ß-globin gene cluster resides in the chromosome region 11p15.5, harboring important immunity genes and IGF2, H19, PHLDA2/TSSC3, TRIM3, and SLC22A18 genes associated with cancers and gliomas. 11p15.5 is a prominent region subject to epigenetic regulation. Thus the ß-globin loci may exert haplotypal interactions with these. Some clues support this theory. It is well established that iron load induces liver cancer in thalassemia major; however iron load-independent associations also exist. Enhanced rates of hematologic malignancies are associated with HB Lepore, association of hemoglobin E with cholangiocarcinoma, and enhanced gastric cancer rates in the thalassemia trait. In the African Herero population, a mutant form of δ-globin is very prevalent, and this population has higher rates of pediatric brain tumors. Globins are also expressed in healthy endothelia and in tumoral vessels, indicating potential involvement in angiogenesis. Studies on HBs and their cleavage peptides in cancers and brain tumors may lead to innovative treatment strategies.

Association between smoking and cognitive impairment in multiple sclerosis.

PURPOSE: Although smoking is known to cause various symptoms in multiple sclerosis (MS) patients, there have been no reports regarding the relationship between smoking and cognitive impairment in MS. Studying the effects of cigarette smoking in MS patients is imperative as there is a high prevalence of cognitive impairment in MS patients. In this study we examined the potentially deleterious effects of heavy smoking on mentation of patients with MS. PATIENTS AND METHODS: MS patients receiving care at the Neurology Clinic at Bezmialem Vakif University, between the ages of 18-65 years who have at least graduated elementary school were included in the study. The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) is a commonly used method to assess cognitive function in MS patients and was utilized in our study. Patients that smoked for at least 10 pack-years were considered heavy smokers. RESULTS: ALL THE PATIENTS WERE STRATIFIED INTO TWO GROUPS: heavy smokers (n=20) and nonsmokers (n=24). For heavy smokers, their cognitive functioning was more impaired than that of nonsmokers (P=0.04, χ (2)=4.227). For patients with cognitive impairment, 78.9% of the Paced Auditory Serial Addition Test and 63.2% of the Symbol Digit Modalities Test scores were found to be lower. CONCLUSION: Previous reports have suggested that smoking increases the frequency of relapse among individuals with relapsing-remitting MS and accelerates disease progression in patients with progressive MS. According to the results of our study, heavy smokers had increased cognitive impairment when compared to nonsmokers. Extensive studies are necessary to further elucidate the relationship between smoking and cognitive impairment in MS patients.

Multiple sclerosis presents with psychotic symptoms and coexists with hypertrophic cardiomyopathy.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. Psychiatric symptoms are not infrequent during MS, yet onset of MS with psychosis is rarely encountered. A 27-year-old Caucasian male was admitted due to numbness in his right arm and difficulty in walking. His clinical and laboratorial exams lead to the MS diagnosis. Nine months earlier, he also developed psychotic disorder, not otherwise specified (PD-NOS). His sudden onset of PD-NOS, his rapid and complete response to antipsychotics, and a relatively short interval between psychiatric and neurological signs indicate a high likelihood that PD-NOS was a manifestation of underlying MS. He also suffers from hypertrophic obstructive cardiomyopathy (HOCM). The patient's neurological complaints were recovered with methylprednisolone (1 g/day, i.v.) given for five days. Glatiramer acetate (1 × 1 tb.s.c.) was prescribed for consolidation and, after nine months of his admission, the patient fully recovered from neurological and psychiatric complaints. Interestingly, very recent studies indicate specific alpha-actinin antibodies in MS and alpha-actinin mutations cause HOCM. Thus, concurrence of MS with HOCM can be even a new syndrome, if further genetic studies prove.

Minor hemoglobins HbA2 and HbF associate with disease severity in bipolar disorder with a likely protective role of HbA2 against post-partum episodes.

BACKGROUND: There exist studies indicating that bipolar disorder (BD) associates with changes in brain blood flow. Human brain with its high demand to oxygen constitutes 2% of the total body weight, while it receives 20% of cardiac output. α and ß globin chains of hemoglobin were recently found in neural tissues, yet no study has questioned blood hemoglobins in BD. METHODS: A total of 120 euthymic BD patients (40 males and 80 females) were analyzed via high performance liquid chromatography (HPLC) to measure minor hemoglobin levels, which were statistically compared with disease characteristics. RESULTS: Minor hemoglobins HbA2 and HbF associated positively with episode density as a measure of disease severity in BD. An increased level of HbA2 meant significantly less postpartum episodes in child bearing women. HbF levels were higher in patients with a positive family history of any psychotic disorder. Sum of HbA2 and HbF correlated with episode density with a stronger significance (p<0.001) supporting intermittent hypoxia hypothesis in BD. LIMITATIONS: The study was conducted only on euthymic patients to avoid likely bigger exogenous effects such as electro-convulsive therapy and diverse drug regimes, yet larger comparative studies are needed to support our current findings. CONCLUSIONS: Higher HbA2 and HbF in more severe bipolar disorder may be compensations against intermittent hypoxias in BD. HbA2 increases following myocardial angina and in mountain dwellers, which may indicate protective roles in extreme conditions. HbF increase may act more as a maladaptation or emerge via haplotypal associations of BD genes and gamma-globin locus at 11p15.5.

[The treatment of bipolar disorder during pregnancy and the postpartum period]. / Gebe ve Lohusalarda Iki Uçlu Bozuklugun Sagaltimi.

The prevalence of bipolar disorder (BD) in males and females is almost equal. The onset of BD in females typically occurs during the reproductive years, complicating its treatment. Although it was once believed that pregnancy prevents recurrence, studies have shown that recurrence is common and severe during pregnancy. On the other hand, the effects of pharmacological treatment on obstetrical outcome are not well known and some of these agents are considered teratogenic. Thus, the decision to treat pregnant patients with psychotropic agents requires solving an ethical dilemma. Risk-benefit decisions should be made while considering both the risk of relapse of BD and its morbidity, and the risk of fetal exposure to psychotropic medications. Moreover, the risk of recurrence increases dramatically in the postpartum period. It is well known that all of the psychotropic medications studied enter the breast milk. Thus, their effects on infants should be considered while prescribing for a breastfeeding mother. The aim of this review was to discuss the safety profiles of the treatment options for pregnant and breastfeeding BD patients. Firstly, each medication's effects on organ dysgenesis, neonatal toxicity, and neurobehavioral development, and their associated adverse events during pregnancy and the postpartum period are discussed, with a focus on the emerging literature. Given this background, practical suggestions on tailoring treatment in BD patients, from preconception to breastfeeding are highlighted.