Gene expression analysis of MAOA and the clock gene ARNTL in individuals with bipolar disorder compared to healthy controls.

INTRODUCTION: Circadian rhythms are associated with bipolar disorder (BD). This cross-sectional study aimed at investigating ARNTL and MAOA gene expression differences (1) between individuals with BD and controls, (2) between affective episodes, and (3) the relationship between ARNTL and MAOA expression. METHODS: ARNTL and MAOA gene expression in peripheral mononuclear blood cells were analysed from fasting blood samples (BD n = 81, controls n = 54) with quantitative real-time PCR operating on TaqMan® assays (normalised to 18S RNA expression). ANCOVAs corrected for age, sex, body mass index, and medication was used to evaluate expression differences and correlation analyses for the relation between ARNTL and MAOA expression. RESULTS: ARNTL gene expression differed between affective episodes (F(2,78) = 3.198, p = 0.047, Partial Eta2= 0.083), but not between BD and controls (n.s.). ARNTL and MAOA expression correlated positively in BD (r = 0.704, p < 0.001) and in controls (r = 0.932, p < 0.001). MAOA expression differed neither between BD and controls nor between affective episodes (n.s.). DISCUSSION: Clock gene expression changes were observed in different affective states of BD. More precisely, ARNTL gene expression was significantly higher in euthymia than in depression. ARNTL and MAOA gene expression correlated significantly in BD and in controls, which emphasises the strong concatenation between circadian rhythms and neurotransmitter breakdown.

The association between anti-inflammatory effects of long-term lithium treatment and illness course in Bipolar Disorder.

INTRODUCTION: Altered levels of acute-phase proteins are often described in different conditions in BD. Nevertheless, data on the association between lithium treatment and inflammatory markers in the long-term course of BD are still missing. The aim of the study was to examine the long-term course of BD concerning long-term lithium treatment, chronic inflammatory processes and symptom progression. Furthermore, the association between duration of lithium treatment and levels of hsCRP was explored. METHODS: 267 individuals (males= 139, females= 128) with BD were included. Duration of lithium treatment as well as symptom progression, defined as the increase in severity of symptoms, number of episodes a year and duration of episodes within a period of 1.5 years in the past and hsCRP were evaluated. RESULTS: Male individuals with symptom progression over time had significantly lower duration of lithium treatment compared to individuals without symptoms progression (U= 47.4, p=.037). There were significantly higher levels of hsCRP in male individuals with symptom progression compared to males without symptom progression (U= 47.5, p=.027). Further, there was a significant negative correlation between the duration of lithium treatment and hsCRP levels in the whole sample (r= -.276, p<.05). CONCLUSION: Our results show that an altered inflammatory state may be associated with a more severe illness course in BD. Further, a longer duration of lithium treatment may be associated with lower symptom progression. The shown association between hsCRP-levels and lithium treatment duration suggests a potential anti-inflammatory effect of lithium as a mediator of its significant positive outcome effect in BD.

Lower cognitive reappraisal capacity is related to impairments in attachment and personality structure in poly-drug use: an fMRI study.

Insecure attachment, impaired personality structure and impaired emotion regulation figure prominently in substance use disorders. While negative emotions can trigger drug-use and relapse, cognitive reappraisal may reduce emotional strain by promoting changes in perspective. In the present study, we explored behavioral and neural correlates of cognitive reappraisal in poly-drug use disorder by testing individuals' capability to generate cognitive reappraisals for aversive events (Reappraisal Inventiveness Test). 18 inpatients with poly-drug use disorder and 16 controls completed the Adult Attachment Scale, the Emotion Regulation Questionnaire, the Brief Symptom Inventory, the Wonderlic Personnel Test, and the Operationalized Psychodynamic Diagnosis Structure Questionnaire, as well as two versions of the Reappraisal Inventiveness Test (during fMRI and outside the lab). Compared to controls, polydrug inpatients reported impaired personality structure, attachment and emotion regulation abilities. In the Reappraisal Inventiveness Test, poly-drug inpatients were less flexible and fluent in generating reappraisals for anger-eliciting situations. Corresponding to previous brain imaging evidence, cognitive reappraisal efforts of both groups were reflected in activation of left frontal regions, particularly left superior and middle frontal gyri and left supplemental motor areas. However, no group differences in neural activation patterns emerged. This suggests that despite cognitive reappraisal impairments on a behavioral level, neural reflections of these deficits in poly-drug use disorder might be more complex.

The relationship between "Eyes Reading" ability and verbal memory in bipolar disorder.

In psychiatric disorders, neurocognitive impairments are prevalent and have been associated with poor outcome. Deficits in Theory of Mind (ToM, "mentalising") have also been observed in bipolar disorder (BD); however, the literature shows inconsistent data. The aim of this study was to explore ToM performance in a well-characterized sample of euthymic individuals with BD and its relationship with neurocognitive function. One hundred sixteen euthymic patients with BD between 18 and 74 years (mean age = 42.4, SD = 13.8) and 79 healthy controls (mean age = 39.8, SD = 16.5) were investigated with an extensive neurocognitive test battery (Trail Making Test A/B, d2 Test of Attention, Stroop Color-Word Test, California Verbal Learning Test, Multiple Choice Vocabulary Test). Additionally, all participants were given the Reading the Mind in the Eyes Test (RMET) to measure affective ToM, the ability to make assumptions about other people´s feelings. Overall, "Eyes Reading" performance was not impaired in individuals with BD compared with controls. However, a significant relationship between RMET and verbal memory in BD was shown, particularly in males. Data showed worse RMET performance in patients with memory deficits compared to patients without memory deficits and controls. Due to cross-sectional data, no conclusions can be made with respect to cause and effect.

Epigenetics of the molecular clock and bacterial diversity in bipolar disorder.

Objectives The gut microbiome harbors substantially more genetic material than our body cells and has an impact on a huge variety of physiological mechanisms including the production of neurotransmitters and the interaction with brain functions through the gut-brain-axis. Products of microbiota can affect methylation according to preclinical studies. The current investigation aimed at analyzing the correlation between gut microbiome diversity and the methylation of the clock gene ARNTL in individuals with Bipolar Disorder (BD). Methods Genomic DNA was isolated from fasting blood of study participants with BD (n = 32). The methylation analysis of the ARNTL CG site cg05733463 was performed by bisulfite treatment of genomic DNA with the Epitect kit, PCR and pyrosequencing. Additionally, DNA was extracted from stool samples and subjected to 16S rRNA sequencing. QIIME was used to analyze microbiome data. Results Methylation status of the ARNTL CpG position cg05733463 correlated significantly with bacterial diversity (Simpson index: r= -0.389, p = 0.0238) and evenness (Simpson evenness index: r= -0.358, p = 0.044). Furthermore, bacterial diversity differed significantly between euthymia and depression (F(1,30) = 4.695, p = 0.039). Discussion The results of our pilot study show that bacterial diversity differs between euthymia and depression. Interestingly, gut microbiome diversity and evenness correlate negatively with methylation of ARNTL, which is known to regulate monoamine oxidase A transcription. We propose that alterations in overall diversity of the gut microbiome represent an internal environmental factor that has an epigenetic impact on the clock gene ARNTL which is thought to be involved in BD pathogenesis.

Increased attachment security is related to early therapy drop-out in substance use disorders.

OBJECTIVES: Previous research work suggests a positive association between secure attachment and increased therapy adherence (TA) in different patient groups. However, there is still a strong need for research focusing on the influence of attachment on TA in substance use disorder (SUD) treatment. Hence, this study attempts to investigate the predictive value of different attachment patterns concerning TA in SUD inpatients. RESULTS: 122 (34 female) SUD inpatients completed the Attachment Style Questionnaire (ASQ) during the entry phase of therapeutic community treatment. After 6 weeks, subjects who remained in therapy (n = 47) completed the ASQ for a second time. In line with the literature, agglomerative Cluster Analysis suggested a two-cluster solution (Cluster I: increased secure attachment pattern; Cluster II: increased insecure attachment pattern). Notably, inpatients in Cluster I were more likely to drop out of treatment within the first 6 weeks (p < .001). Furthermore, subjects showed less "Confidence in Self and Others" (p < .05) after 6 weeks of treatment. Our findings indicate a negative predictive value of increased attachment security for TA in SUD inpatients. This finding probably mirrors a more realistic kind of self-assessment. More generally, the importance of considering attachment styles in SUD treatment is underlined.

The role of tryptophan metabolism and food craving in the relationship between obesity and bipolar disorder.

BACKGROUND & AIMS: Individuals with bipolar disorder (BD) have a significantly increased risk of obesity-related conditions. The imbalance between food intake and energy expenditure is assumed to be a major risk factor for obesity in BD. This study analyzed food craving in relation to anthropometric, metabolic, and neurobiological parameters in a well-characterized cohort of euthymic individuals with BD. METHODS: One-hundred-thirty-five patients completed the Food-Craving Inventory assessing four categories of food craving (fat, fast-food, sweets and carbohydrate craving). Additionally, clinical, metabolic and anthropometric parameters were assessed. RESULTS: Higher levels of fat craving were observed in males, versus females, with BD. High levels of carbohydrate craving positively correlated with kynurenine and the kynurenine-to-tryptophan ratio. Higher serum nitrite and neopterin levels were related to fat craving. Parameters of fat metabolism (triglycerides, high-density lipoprotein) were associated with fat and fast-food craving. Anthropometric measures of obesity (e.g. body mass index, waist-to-hip-ratio) were not related to food craving. CONCLUSIONS: Overweight/obese individuals with BD show an increased driving of tryptophan down the kynurenine pathways, as indicated by an increase in the serum kynurenine-to-tryptophan ratio. The driving of tryptophan down the kynurenine pathway is mediated by immune-inflammatory activity and stress. The correlation of increased kynurenine with food craving, especially carbohydrate craving, probably indicates a regulatory deficit in the maintenance of chronic inflammatory processes in obesity and BD. Food craving seems to be of clinical importance in the treatment of metabolic disturbances in BD, although not associated with anthropometric measures of obesity. Rather, food craving correlates with blood metabolic parameters and an increased activation of the kynurenine pathway, both of which are linked to higher affective symptomatology and the development of cardiovascular diseases.

[Addiction as an attachment disorder]. / Sucht als Bindungsstörung.

BACKGROUND: There is no commonly accepted model for describing the development and treatment of substance use disorders (SUD); however, over several decades the attachment theory has represented an important basis for the clinical handling of SUD. This study gives a systematic review of empirical studies regarding the relationship between SUD and disorders of attachment behavior. OBJECTIVE: Is there a positive relationship between disorders of attachment behavior and the presence of SUD? METHOD: Various databases (PsychInfo, Web of Science, PubMed) were systematically searched in order to pinpoint relevant studies in books and articles published in English or German. Based on the results 22 publications were selected. After a stricter limitation to original research, 12 articles could finally be accepted as eligible. RESULTS: A significant relationship was found between SUD and insecure attachment in 10 out of the 12 studies. CONCLUSION: Based on the results of the research studies reviewed the hypothesis to characterize SUD as a possible expression of an attachment disorder was confirmed. This corroborates the importance of considering attachment parameters in dealing with prevention and treatment of SUD. Further research might focus on non-substance-related addictive disorders and therapy outcome studies.

[Factitious disorders]. / Artifizielle Störungen.

Patients with factitious disorders intentionally fabricate, exaggerate or feign physical and/or psychiatric symptoms for various open and covert psychological reasons. There are many issues regarding the diagnostic state and classification of factitious disorders. Both the categorical differentiation of and clinical continuum ranging from somatoform/dissociative disorders to malingering are being controversially debated. Epidemiological studies on the frequency of factitious disorder meet basic methodological difficulties. Reported rates of prevalence and incidence in the professional literature most probably have to be considered underestimations. Illness deception and self-harm as core features of the abnormal illness behaviour in factitious disorder may refer to various highly adverse and traumatic experiences during early development in a subgroup of patients. Chronic courses of illness prevail; however, there are also episodic variants.

[Depressive, anxiety and posttraumatic stress disorders as long-term sequelae of intensive care treatment]. / Depressive, Angst- und posttraumatische Belastungsstörungen als Konsequenzen intensivmedizinischer Behandlung.

Modern intensive care medicine has led to increased survival rates even after severe life-threatening medical conditions. In self-critical and multidimensional outcome research, however, it must be considered that beyond survival rates treatment on intensive care units (ICU) can also be associated with high long-term rates of depressive, anxiety and posttraumatic stress disorders. Significant correlations with increased somatic morbidity and mortality, persisting cognitive impairments and significant deficits in health-related quality of life must also be taken into consideration. Empirical analysis of the risk factors reveals that a history of premorbid depression, sociodemographic and socioeconomic variables, age, female sex, personality traits, the underlying pathophysiological condition requiring ICU treatment, mode of sedation and analgesia, life support measures, such as mechanical ventilation, manifold traumatic experiences and memories during the stay in the ICU are all of particular pathogenetic importance. In order to reduce principally modifiable risk factors several strategies are illustrated, including well-reflected intensive care sedation and analgesia, special prophylactic medication regarding the major risk of traumatic memories and posttraumatic stress disorder (PTSD), psychological and psychotherapeutic interventions in states of increased acute stress symptoms and aids for personal memories and reorientation.

White matter integrity in polydrug users in relation to attachment and personality: a controlled diffusion tensor imaging study.

The relationship between substance use disorders (SUD) and brain deficits has been studied extensively. However, there is still a lack of research focusing on the structural neural connectivity in long-term polydrug use disorder (PUD). Since a deficiency in white matter integrity has been reported as being related to various parameters of increased psychopathology, it might be considered an aggravating factor in the treatment of SUD. In this study we compared two groups of PUD inpatients (abstinent: n = 18, in maintenance treatment: n = 15) to healthy controls (n = 16) with respect to neural connectivity in white matter, and their relation to behavioral parameters of personality factors/organization and attachment styles. Diffusion Tensor Imaging was used to investigate white matter structure. Compared with healthy controls, the PUD patients showed reduced fractional anisotropy (FA) and increased radial diffusivity (RD) mainly in the superior fasciculus longitudinalis and the superior corona radiata. These findings suggest diminished neural connectivity as a result of myelin pathology in PUD patients. In line with our assumptions, we observed FA in the biggest cluster as negatively correlated with anxious attachment (r = 0.36, p < 0.05), personality dysfunctioning (r = -0.41; p < 0.01) as well positively correlated with personality factors Openness (r = 0.34; p < 0.05) and Agreeableness (r = 0.28; p < 0.05). Correspondingly these findings were inversely mirrored by RD. Further research employing enhanced samples and addressing longitudinally neuronal plastic effects of SUD treatment in relation to changes in personality and attachment is recommended.

Abdominal obesity is associated with impaired cognitive function in euthymic bipolar individuals.

OBJECTIVES: Overweight/obesity has been implicated to play a role in cognitive deficits in bipolar disorder (BD). This study aims to identify the relationship between body fat distribution and different domains of cognition in BD during euthymia. METHODS: A sample of 100 euthymic individuals with BD was measured with a cognitive test battery (i.e., Trail Making Test-A-B/TM-A/B, d2 Test of Attention, Stroop test, California Verbal Learning Test/CVLT) and an anthropometric measures set (body mass index, waist circumference, hip circumference, waist-to-hip-ratio, waist-to-height-ratio, and lipometry). Patient data were compared with a healthy control group (n = 64). RESULTS: Results show that overweight patients with BD exhibit lower performance in the TMT-A/B as well as in the free recall performance of the CVLT compared to normal-weight patients with BD and controls. In bipolar individuals, (abdominal) obesity was significantly associated with a poor cognitive performance. In bipolar females, associations with measures of verbal learning and memory were found; in bipolar males, associations with poor performance in the TMT-A/B and in the Stroop interference task were demonstrated. In controls, no associations were found. CONCLUSIONS: There are several possible pathways moderating the association between obesity and cognition in BD. Anthropometric and lipometry data underline the substantial mediating impact of body fat distribution on cognition in BD.

[Tizanidine withdrawal symptoms in stress cardiomyopathy]. / Tizanidin-Absetzsymptome bei Stress-Kardiomyopathie.

INTRODUCTION: An acute discontinuation of tizanidine, an alpha-2-agonistic muscle relaxant, is associated with reflex tachycardia, hypertension, tremor, hypertonicity and anxiety. CASE REPORT: We describe a 53-year-old patient with broken-heart syndrome, who developed serious tizanidine withdrawal symptoms after high-dosed long-term treatment within the framework of stress cardiomyopathy. CONCLUSION: Central muscle relaxants like tizanidine might have an impact on the development of delirium. Tizanidine withdrawal should be considered in patients who manifest signs and symptoms of withdrawal from medications. The drug should be gradually reduced in dosage under observation by a psychiatrist. When prescribing tizanidine, the possible pharmacological side effects and interactions should be taken into careful account.

[Comorbid depressive and anxiety disorders in patients with cancer]. / Depressive und Angststörungen bei Krebserkrankungen.

Patients with cancer face a high risk of comorbid depressive and anxiety disorders that have to be paradigmatically considered within a complex biopsychosocial context. Several conceptual challenges have to be mastered in arriving at a correct clinical diagnosis. Coexistent affective and anxiety disorders in cancer patients include a more dramatic subjective suffering, reduced psychological coping, possible negative interference with somatic treatment and rehabilitation, impaired quality of life and higher grades of psychosocial disability. They may also lead to an overall increased risk of somatic morbidity, a more rapid progression of cancer and a higher cancer-related mortality in the course of the disease. Manifold psychological, psychosocial and existential, cancer and treatment-related stressors have to be considered with respect to common neurobiological, especially neuroendocrine and neuroinflammatory mechanisms. Complex psychosomatic, somatopsychic and somato-somatic effects must always be considered. Evidence-based approaches in psychotherapy and pharmacotherapy exist for the integrative treatment of comorbid depressive and anxiety disorders in cancer.

[Spirituality in schizophrenic diseases]. / Spiritualität bei schizophrenen Erkrankungen.

OBJECTIVE: The aim of this study was to investigate different dimensions of religiosity and spirituality among schizophrenic inpatients (F 2x) compared to addiction patients (F 10.2, F 19.2) and to healthy controls. In addition the dimensions of religious and spiritual well-being were examined and related to different parameters of mental illness. METHOD: The group of schizophrenic patients (n = 39) was compared to a group of addiction patients (n = 33) and a healthy control group (n = 38) by means of the multidimensional inventory for religious/spiritual well-being (MI-RSWB). Additionally, dimensions of RSWB were related to the Beck depression inventory (BDI) and the brief symptom inventory (BSI) in the group of schizophrenic patients. RESULTS: The group of schizophrenic patients did not differ from the addiction patients or from the healthy controls in the RSWB dimensions, except for the hope transcendent sub-dimension. Furthermore, dimensions of RSWB turned out to be negatively correlated with the severity of psychiatric symptoms (BDI and BSI). CONCLUSION: As assumed a positive relationship between RSWB and subjective well-being can be confirmed also for the group of schizophrenic patients. Existentially oriented dimensions such as hope and forgiveness might be specifically relevant for the group of schizophrenics.

Peripheral markers of oxidative stress and antioxidative defense in euthymia of bipolar disorder--Gender and obesity effects.

INTRODUCTION: Oxidative and nitrosative stress are implicated in the pathogenesis of uni- and bipolar disorder. Herein we primarily sought to characterize markers of oxidative/nitrosative stress during euthymia in adults with bipolar disorder (BD). Oxidative markers were further evaluated in this BD sample in synopsis with excess overweight or obesity and/or comorbid metabolic syndrome (MetS). METHODS: Peripheral markers of oxidative stress [i.e. thiobarbituric acid reactive substance, (TBARS), malondialdehyde (MDA), and carbonyl proteins] and antioxidant markers [e.g. total antioxidative capacity (TAC), superoxide dismutase (SOD), glutathione S-transferase (GST)] were obtained in a cohort of euthymic adults with BD (N=113) and compared to healthy controls (CG) (N=78). Additionally, anthropometric measures included the body mass index (BMI) [kg/m(2)], waist and hip circumference [cm], waist-to-hip-ratio (WHR), waist to height ratio (WtHR) as well as the IDF-defined MetS. RESULTS: The major finding was a significantly decreased TAC in BD compared to the CG (p<0.01; BD: M 1.18, SD 0.47; CG: M 1.39, SD 0.49). MDA was significantly and TBARS by trend higher in the CG compared to the euthymic bipolar test persons (MDA: p<0.01, BD: M 0.70, SD 0.18; CG: M 0.81, SD 0.25; TBARS: p<0.1, BD: M 0.78, SD 0.28; CG: M 0.76, SD 0.30). The antioxidative enzyme GST was significantly elevated in both patients and controls (BD: M 298.24, SD 133.02; CG: M 307.27 SD 118.18). Subgroup analysis revealed that the CG with concurrent MetS and obesity had significantly elevated TAC when compared to CG without concurrent MetS (p<0.05, no MetS: M 1.33, SD 0.50; MetS: M 1.67, SD 0.32), as well as persons with BD with or without current MetS (no MetS: M 1.18, SD 0.44; MetS: M 1.15, SD 0.49). Significant correlations between GST and anthropometric variables were found in male study participants. Multivariate analysis indicated a significant gender effect concerning TBARS values in all patients and CG (p<0.01, females: M 0.73, SD 0.29; males: M 0.83, SD 0.28). CONCLUSION: Euthymic bipolar adults exhibit peripheral evidence of a disturbed biosignature of oxidative stress and antioxidative defense. Male test persons showed significantly higher peripheral markers of oxidative stress than women- female sex may exert protective effects. Furthermore, the biosignature of oxidative stress obtained herein was more pronounced in males with concurrent metabolic disorders. Our results further extend knowledge by introducing the moderating influence of gender and obesity on oxidative stress and BD.

[Rapid cycling--finally stable but obese--target acquired?]. / Rapid Cycling--Endlich stabil aber adipös--Ziel erreicht?

Overweight and obesity are common in patients with bipolar disorder. Rates of up to 70% are described in scientific publications. There is sufficient evidence that these conditions are associated with a worse course of the disease (more episodes, higher suicide and hospitality rates, worse response to lithium, somatic comorbidities). Most of the mood stabilisers lead to weight gain. This is also true for clozapine, which can be effective in therapy-refractory courses of bipolar disorder. This case report demonstrates the complexity of the treatment of bipolar disorder. A young patient in depressive stupor following a severe suicide attempt after 5 months of hospital treatment was sent to our department to perform ECT. This was not possible because of the severity of his injuries. We were able to cure the acute condition and interrupt the course of rapid cycling with a combination of clomipramine, lithium and clozapine. A stable course of four years under this medication and psychoeducation has been achieved. In this period the patient was able to lower his body mass index from 38 to 26 because of a consequent lifestyle modification.