Genetic and functional analyses implicate microRNA 499A in bipolar disorder development.

Bipolar disorder (BD) is a complex mood disorder with a strong genetic component. Recent studies suggest that microRNAs contribute to psychiatric disorder development. In BD, specific candidate microRNAs have been implicated, in particular miR-137, miR-499a, miR-708, miR-1908 and miR-2113. The aim of the present study was to determine the contribution of these five microRNAs to BD development. For this purpose, we performed: (i) gene-based tests of the five microRNA coding genes, using data from a large genome-wide association study of BD; (ii) gene-set analyses of predicted, brain-expressed target genes of the five microRNAs; (iii) resequencing of the five microRNA coding genes in 960 BD patients and 960 controls and (iv) in silico and functional studies for selected variants. Gene-based tests revealed a significant association with BD for MIR499A, MIR708, MIR1908 and MIR2113. Gene-set analyses revealed a significant enrichment of BD associations in the brain-expressed target genes of miR-137 and miR-499a-5p. Resequencing identified 32 distinct rare variants (minor allele frequency < 1%), all of which showed a non-significant numerical overrepresentation in BD patients compared to controls (p = 0.214). Seven rare variants were identified in the predicted stem-loop sequences of MIR499A and MIR2113. These included rs142927919 in MIR2113 (pnom = 0.331) and rs140486571 in MIR499A (pnom = 0.297). In silico analyses predicted that rs140486571 might alter the miR-499a secondary structure. Functional analyses showed that rs140486571 significantly affects miR-499a processing and expression. Our results suggest that MIR499A dysregulation might contribute to BD development. Further research is warranted to elucidate the contribution of the MIR499A regulated network to BD susceptibility.

The impact of attachment parameters in childhood on the personality of adults with mental disorders.

BACKGROUND: Attachment parameters have an effect on later relationship patterns and the development of parameters of self-concept and personality. In the current study the role of attachment parameters on personality dimensions was investigated, especially with respect to personality disorders. SUBJECTS AND METHODS: 134 psychiatric inpatients were examined on attachment and personality parameters using the schedule FEB as a questionnaire on the parental attachment and the SKI as a self-concept inventory. RESULTS: Regression and correlation analyses suggest positive influences of parental care and negative influences of parental overprotection on the development of ego-strength in adulthood. Patients with personality disorders reported to have experienced less maternal care during their childhood and showed a trend towards a reduced ego-strength in adulthood compared to patients with others mental disorders. CONCLUSIONS: Relationships of attachment parameters in childhood with personality dimension are explorable. This approach seems meaningful for a better understanding of the development of personality disorders. Clinicians should be familiar with attachment patterns when treating people with mental disorders in order to adequately include appropriate personality dimensions in the therapy.

The effects of music therapy on the interaction of the self and emotions-An interim analysis.

OBJECTIVES: Music therapy is a well-established non-verbal treatment method in psychiatry and psychosomatic medicine. However, empirical data of its impact on emotion modulation processes and personality dimensions are still sparce. An interesting concept is the use of music for emotion modulation in everyday life. The purpose of this interim study was to assess the interplay of personality dimensions and emotion modulation strategies in patients treated with music therapy versus patients without music therapy. DESIGN: A cross-sectional design was used. SETTING: The study was conducted during the course of inpatient treatment in a general psychiatric hospital. Data from n = 137 patients was included in the analysis. MAIN OUTCOME MEASURES: According to the mediator model a regression analysis was performed using personality variables as potential predictors and emotion modulation variables as outcome criteria. RESULTS: In the music therapy group, insecurity predicted the use of music for both cognitive problem solving and positive stimulation in everyday life. In the non-music therapy group, cooperation and insouciance predicted the use of music for reduction of negative activation. CONCLUSIONS: Specific personality dimensions predict greater targeted emotion modulation strategies if music therapy is applied than without it. That is, music therapy helps patients acquire more conscious (i.e. cognitive-related strategies) emotion modulation techniques by means of including their individual personality, whereas patients without music therapy simply "vent" their negative emotions (i.e. non-cognitive strategies). Conversely, the data suggest that music therapy can contribute to modify personality dimensions through the development of these emotion modulation strategies. This could be a plausible explanation for beneficial long-term effects of music therapy.

Hydrogen Sulfide Affects Radical Formation in the Hippocampus of LPS Treated Rats and the Effect of Antipsychotics on Hydrogen Sulfide Forming Enzymes in Human Cell Lines.

Objectives: Psychiatric disorders, such as schizophrenia and other neuroinflammatory diseases are accompanied by an increase in the oxidative stress and changes in the immune system and in the metabolic, hormonal and neurological components of the central nervous system (CNS). Hydrogen sulfide (H2S) is a gaseous molecule that is endogenously produced in the peripheral and central nervous system through cysteine by the following major H2S producing enzymes in the brain: cystathionine-γlyase (CSE), cystathionine ß-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MPST). The physiological effects of H2S are broad, with antioxidative properties being a major role in the body. The aims of our investigation were to analyze the central nervous antioxidant, metabolic and neuronal effects in the hippocampus of the rat after inflammatory peripheral lipopolysaccharide (LPS) treatment; and to examine the effects of antipsychotics on the expression of these enzymes in human cell lines. Material and Methods: Male Lewis rats (250 g) received an i.p. LPS injection (1 mg/kg) 24 h before microdialysis experiments. Conscious rats were infused via these probes (1.5 µl/min) with a radical scavenger 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine (CMH) in Krebs-Ringer solution. Sodiumhydrogensulfide (NaHS, 10 µg/min) was infused after a 2- h baseline for 1 h. Corticosterone, glutamate, glucose and lactate were measured by Elisa. Reactive oxygen species (ROS) were detected by electron spin resonance spectroscopy (ESR). The impact of the antipsychotics haloperidol, clozapine, olanzapine and risperidone on the expression of genes encoding the key enzymes of H2S synthesis was studied at the human neuroblastoma SH-SY5Y and monocytic U-937 cell lines. The cells were incubated for 24 h with 30 µM antipsychotic following which mRNA levels were measured by polymerase chain reaction. Results: Microdialysate glucose and lactate levels dramatically increased in the hippocampus of LPS untreated rats by local application of NaHS. By contrast, in the LPS pretreated rats, there was no effect of NaHS infusion on glucose but a further significant increase in microdialysate lactate was found. It was LPS pretreatment alone that particularly enhanced lactate levels. There was a marked increase in hippocampal microdialysate glutamate levels after local NaHS infusion in LPS untreated animals. In LPS treated rats, no change was observed by NaHS, but LPS itself had the strongest effect on microdialysate glutamate levels. Microdialysate corticosterone levels were reduced by NaHS in both LPS pretreated and untreated rats. The formation of free radicals in the hippocampus significantly reduced in LPS pretreated rats, while in LPS untreated rats a significant increase was observed after NaHS infusion. In human SH-SY5Y and U-937 cells, all three major enzymes of H2S-Synthesis, namely cystathionine-γ-lyase, cystathione ß-synthase and 3-mercaptopyruvate sulfurtransferase, could be detected by PCR. The antipsychotics haloperidol, clozapine, olanzapine and risperidone affected all three enzymes in different ways; with haloperidol and risperidone showing major effects that led to reductions in CBS or CSE expression. Discussion: The local application of NaHS in the hippocampus of the rat strongly affected glucose, lactate and glutamate release. Contrastingly, in LPS pretreated rats, a decreased radical formation was the only effect found. H2S synthetizing enzymes may be involved in antipsychotic mechanisms, although no clear common mechanism could be found.

Identification of shared risk loci and pathways for bipolar disorder and schizophrenia.

Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.

Internet-Delivered Disease Management for Recurrent Depression: A Multicenter Randomized Controlled Trial.

BACKGROUND: Strategies to improve the life of patients suffering from recurrent major depression have a high relevance. This study examined the efficacy of 2 Internet-delivered augmentation strategies that aim to prolong symptom-free intervals. METHODS: Efficacy was tested in a 3-arm, multicenter, open-label, evaluator-blind, randomized controlled trial. Upon discharge from inpatient mental health care, 232 adults with 3 or more major depressive episodes were randomized to 1 of 2 intervention groups (SUMMIT or SUMMIT-PERSON) or to treatment as usual (TAU) alone. Over 12 months, participants in both intervention arms received, in addition to TAU, intense monitoring via e-mail or a smartphone, including signaling of upcoming crises, assistance with personal crisis management, and facilitation of early intervention. SUMMIT-PERSON additionally offered regular expert chats. The primary outcome was 'well weeks', i.e. weeks with at most mild symptoms assessed by the Longitudinal Interval Follow-Up Evaluation, during 24 months after the index treatment. RESULTS: SUMMIT compared to TAU reduced the time with an unwell status (OR 0.48; 95% CI 0.23-0.98) through faster transitions from unwell to well (OR 1.44; 95% CI 0.83-2.50) and slower transitions from well to unwell (OR 0.69; 95% CI 0.44-1.09). Contrary to the hypothesis, SUMMIT-PERSON was not superior to either SUMMIT (OR 0.77; 95% CI 0.38-1.56) or TAU (OR 0.62; 95% CI 0.31-1.24). The efficacy of SUMMIT was strongest 8 months after the intervention. CONCLUSIONS: The fully automated Internet-delivered augmentation strategy SUMMIT has the potential to improve TAU by reducing the lifelong burden of patients with recurrent depression. The fact that the effects wear off suggests a time-unlimited extension.

Coping with delusions in schizophrenia and affective disorder with psychotic symptoms: the relationship between coping strategies and dimensions of delusion.

BACKGROUND: Self-generated coping strategies and the enhancement of coping strategies are effective in the treatment of psychotic symptoms. Evaluating these strategies can be of clinical interest to develop better coping enhancement therapies. Cognitive models consider delusions as multidimensional phenomena. Using a psychometric approach, the relationship between coping and the dimensions of delusion were examined. METHODS: Thirty schizophrenia spectrum patients with delusions and 29 patients with affective disorder with psychotic symptoms were interviewed using the Heidelberg Coping Scales for Delusions and the Heidelberg Profile of Delusional Experience. Analyses of variance were conducted to investigate differences between the groups, and Spearman's rank-based correlations were used to examine the correlations between coping factors and the dimensions of delusion. RESULTS: Schizophrenia spectrum patients used more medical care and symptomatic coping, whereas patients with affective disorder engaged in more depressive coping. In the schizophrenia spectrum sample, the action-oriented, the cognitive, and the emotional dimensions of delusion were related to coping factors. In patients with affective disorder, only the action-oriented dimension was related to coping factors. CONCLUSION: Patients with schizophrenia and affective disorder cope differently with delusions. The dimensions of delusion are related to coping and should be regarded when using cognitive therapy approaches to enhance coping strategies.

Genome-wide association study reveals two new risk loci for bipolar disorder.

Bipolar disorder (BD) is a common and highly heritable mental illness and genome-wide association studies (GWAS) have robustly identified the first common genetic variants involved in disease aetiology. The data also provide strong evidence for the presence of multiple additional risk loci, each contributing a relatively small effect to BD susceptibility. Large samples are necessary to detect these risk loci. Here we present results from the largest BD GWAS to date by investigating 2.3 million single-nucleotide polymorphisms (SNPs) in a sample of 24,025 patients and controls. We detect 56 genome-wide significant SNPs in five chromosomal regions including previously reported risk loci ANK3, ODZ4 and TRANK1, as well as the risk locus ADCY2 (5p15.31) and a region between MIR2113 and POU3F2 (6q16.1). ADCY2 is a key enzyme in cAMP signalling and our finding provides new insights into the biological mechanisms involved in the development of BD.

Supportive monitoring and disease management through the internet: an internet-delivered intervention strategy for recurrent depression.

Major depression is a highly prevalent, disabling disorder associated with loss of quality of life and large economic burden for the society. Depressive disorders often follow a chronic or recurrent course. The risk of relapses increases with each additional episode. The internet-deliverable intervention strategy SUMMIT (SUpportive Monitoring and Disease Management over the InTernet) for patients with recurrent depression has been developed with the main objectives to prolong symptom-free phases and to shorten symptom-loaden phases. This paper describes the study design of a six-sites, three-arm, randomized clinical trial intended to evaluate the efficacy of this novel strategy compared to treatment as usual (TAU). Two hundred thirty six patients who had been treated for their (at least) third depressive episode in one of the six participating psychiatric centers were randomized into one of three groups: 1) TAU plus a twelve-month SUMMIT program participation with personal support or 2) TAU plus a twelve-month SUMMIT program participation without personal support, or 3) TAU alone. Primary outcome of this study is defined as the number of "well weeks" over 24months after index treatment assessed by blind evaluators based on the Longitudinal Interval Follow-Up Evaluation. If efficacious, the low monetary and nonmonetary expenditures of this automated, yet individualized intervention may open new avenues for providing an acceptable, convenient, and affordable long-term disease management strategy to people with a chronic mental condition such as recurrent depression.

Heidelberg Coping Scales for Delusions: psychometric evaluation of an expert rating instrument.

BACKGROUND: Coping is of substantial relevance in the treatment and course of psychiatric disorders. Standardized instruments to assess coping with psychotic symptoms, particularly delusions, are rare. The aim of this study was to develop and evaluate the psychometric properties of a new instrument to assess coping strategies in the context of delusional experiences: the Heidelberg Coping Scales for Delusions (HCSD). METHODS: Two hundred and twelve inpatients with schizophrenia spectrum disorders and affective disorders currently experiencing delusions were interviewed with the HCSD and other coping assessment instruments. Psychometric properties and factor structure were analyzed. RESULTS: The HCSD showed good inter-rater reliability and convergent validity. Factor analysis yielded an interpretable structure with five factors: resource-oriented coping, medical care, distraction, cognitive coping, and depressive coping. Symptomatic behavior, due to its particular characteristics, was considered apart. CONCLUSION: The HCSD is a reliable and valid instrument for the assessment of coping strategies in patients with delusions. Further research is needed to evaluate coping changes over time and their influence on treatment and clinical outcomes.

Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder.

We conducted a genome-wide association study (GWAS) and a follow-up study of bipolar disorder (BD), a common neuropsychiatric disorder. In the GWAS, we investigated 499,494 autosomal and 12,484 X-chromosomal SNPs in 682 patients with BD and in 1300 controls. In the first follow-up step, we tested the most significant 48 SNPs in 1729 patients with BD and in 2313 controls. Eight SNPs showed nominally significant association with BD and were introduced to a meta-analysis of the GWAS and the first follow-up samples. Genetic variation in the neurocan gene (NCAN) showed genome-wide significant association with BD in 2411 patients and 3613 controls (rs1064395, p = 3.02 × 10(-8); odds ratio = 1.31). In a second follow-up step, we replicated this finding in independent samples of BD, totaling 6030 patients and 31,749 controls (p = 2.74 × 10(-4); odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 × 10(-9) (odds ratio = 1.17). Our results provide evidence that rs1064395 is a common risk factor for BD. NCAN encodes neurocan, an extracellular matrix glycoprotein, which is thought to be involved in cell adhesion and migration. We found that expression in mice is localized within cortical and hippocampal areas. These areas are involved in cognition and emotion regulation and have previously been implicated in BD by neuropsychological, neuroimaging, and postmortem studies.

Psychometric evaluation of the Psychotic Symptom Rating Scales.

BACKGROUND: The aims of this study were to examine the psychometric properties of a German version of the Psychotic Symptom Rating Scales (PSYRATS) in a sample of patients with schizophrenic spectrum disorders and affective disorders with delusions and to validate subscales of the PSYRATS with other ratings of psychotic symptoms. SAMPLING AND METHODS: Two hundred patients with schizophrenic spectrum disorder and affective disorders with delusions were examined. Psychometric properties of the PSYRATS items and scales were determined, and the scores of the PSYRATS scales and subscales were compared to the Positive and Negative Syndrome Scale (PANSS) and other ratings of psychotic symptoms. RESULTS: The PSYRATS items and scales were found to have excellent interrater reliability. Two factors for the delusions scale (DS) and 4 factors of the auditory hallucinations scale were found. Subscales of the DS and auditory hallucinations scale were replicated by factor analysis, and the validity of the subscales was supported. CONCLUSIONS: The German version of the PSYRATS is a reliable and valid assessment tool for delusions and hallucinations. The findings support the validity of the PSYRATS subscales. The DS is also applicable for patients with affective disorders.

The effects of oral contraceptives on detection and pain thresholds as well as headache intensity during menstrual cycle in migraine.

BACKGROUND: Clinically, oral contraceptives (OC) can influence pain in both migraine headache and temporomandibular pain disorders. Estrogen as an ingredient of OC might be a responsible factor for these observations. We conducted the present study to test whether OC are able to alter the severity of headache attacks as well as the detection or pain thresholds over the course of the menstrual cycle in patients with migraine. METHODS: Thirteen healthy and regularly menstruating women and 26 migraineurs (13 using OC and 13 not using OC) were studied on the days 1, 4, 14, and 22 of their menstrual cycle. In all participants, saliva was collected first for determination of estrogen on each study day. Then, detection thresholds (warmth, cold, electrical current) and pain thresholds (cold, heat, pressure, electrical current) were assessed. Migraineurs were asked for headache attacks occurring in a period of 24 hours before testing and to estimate pain intensity on a verbal rating scale. RESULTS: On day 4 of the menstrual cycle, migraineurs using OC suffered significantly more from severe migraine attacks than migraineurs not taking OC. With respect to detection and pain thresholds, no effects of OC could be observed as concerning the differences between migraineurs with or without OC medication. On day 22, the severity of migraine headache was significantly related with the pain thresholds for pressure and electrical current, suggesting paradoxically more severe headache attacks in patients presenting with higher pain thresholds. Healthy volunteers disclosed higher salivary estrogen levels than migraineurs and migraineurs not using OC higher concentrations than migraineurs using OC throughout the menstrual cycle. CONCLUSIONS: In this study, the use of OC intensified migraine (however only at the end of menstruation) however had no influence on detection and pain thresholds in migraineurs. Possible reasons for this dissociation will be discussed.

Psychometric evaluation of the characteristics of delusions rating scale as an expert rating scale.

BACKGROUND: Research suggests delusions may be better viewed as multidimensional rather than dichotomous phenomena. The aim of this study was to assess the reliability and validity of a German version of the Characteristics of Delusions Rating Scale (CDRS) as an expert rating scale. METHOD: 200 inpatients with schizophrenic spectrum and affective disorders with delusions were assessed with the CDRS and other delusion rating scales. Factorial validity was analysed, and differences between diagnostic groups on the CDRS subscales as well as on the total score were examined. RESULTS: The CDRS was found to have good inter-rater reliability and internal consistency as an expert rating. Factor analysis yielded an interpretable structure with 3 factors - cognition, emotion and bizarreness - accounting for 70% of the variance. The convergent and differential validity of the scales was supported. Compared to other scales, the CDRS measures all dimensions of delusional experience that have been suggested to date with the exception of behavioural aspects. CONCLUSIONS: The results support the view of delusions as multidimensional phenomena. The CDRS as an expert rating is a reliable and valid assessment tool for dimensions of delusional experience and an economical instrument for research and clinical practice. Further research is needed to examine the dimensional structure underlying delusional phenomena and the relationship of the dimensions to neurobiological and psychotherapeutic processes.

Dimensions of delusional experience scale: a psychometric evaluation of a german version.

BACKGROUND: Delusional experience is a fundamental symptom of psychotic illness. Over recent years, a multidimensional perspective has become increasingly important regarding this phenomenon. Several instruments to measure different dimensions of delusions have been constructed. The aims of this study were to examine the reliability and validity of a German version of the Dimensions of Delusional Experience Scale (DDE). METHODS: Two hundred inpatients with a schizophrenic spectrum disorder or an affective disorder with delusions were examined with the DDE, the Positive and Negative Syndrome Scale (PANSS) and other rating scales for delusional experiences. RESULTS: The scale was found to have good reliability and excellent inter-rater reliability. The 2 factors, delusional involvement and delusional construct, found by Kendler et al. [Am J Psychiatry 1983;140:466-469] could be replicated. The convergent and differential validity of the scale was supported. Besides the content-related aspect 'bizarreness', the DDE mainly assesses cognitive aspects, emotional and behavioral aspects are not incorporated. CONCLUSIONS: The results support the value of a multidimensional perspective of delusional experiences. The German version of the DDE is a reliable and valid assessment tool for different dimensions of delusions, and an economical instrument for research and clinical practice. Further research is needed to reveal the dimensional structure underlying delusional experience.

Impact of haloperidol and quetiapine on the expression of genes encoding antioxidant enzymes in human neuroblastoma SH-SY5Y cells.

Antipsychotics are known to alter antioxidant activities in vivo. Therefore, the aim of the present study was to examine in the human neuroblastoma SH-SY5Y cell line the impact of a typical (haloperidol) and an atypical (quetiapine) antipsychotic on the expression of genes encoding the key enzymes of the antioxidant metabolism (Cu, Zn superoxide dismutase; Mn superoxide dismutase; glutathione peroxidase; catalase) and enzymes of the glutathione metabolism (gamma-glutamyl cysteine synthetase, glutathione-S-transferase, gamma-glutamyltranspeptidase, glutathione reductase). The cells were incubated for 24h with 0.3, 3, 30 and 300microM haloperidol and quetiapine, respectively; mRNA levels were measured by polymerase chain reaction. In the present study, we observed mostly significant decreases of mRNA contents. With respect to the key pathways, we detected mainly effects on the mRNA levels of the hydrogen peroxide detoxifying enzymes. Among the enzymes of the glutathione metabolism, glutathione-S-transferase- and gamma-glutamyltranspeptidase-mRNA levels showed the most prominent effects. Taken together, our results demonstrate a significantly reduced expression of genes encoding for antioxidant enzymes after treatment with the antipsychotics, haloperidol and quetiapine.

Relationships among endocrine and signaling-related responses to antidepressants in human monocytic U-937 blood cells: analysis of factors and response patterns.

OBJECTIVE: Antidepressants (AD) (desipramine, imipramine, maprotiline, mirtazapine) and corticosteroid (CS) were examined for their effects on gene expression in human monocytic U-937 blood cells. Endocrine and signaling-related response patterns were determined by expression analysis of different factors, comprising endocrine (glucocorticoid receptor [GR], GR-alpha/beta/gamma; mineralocorticoid receptor [MR]) and signaling-related pathways (p105, STAT3, c-jun, c-fos, JNK1, GAPDH, TNF-alpha). METHODS: A semiquantitative RT-PCR for factor responses after 24 h of treatment was conducted and exploratory multivariate statistical procedures were applied for further analysis. RESULTS: Compared to controls, significant reduction of mRNA levels of GR-beta under imipramine and of c-jun under desipramine treatment were found. CS treatment significantly reduced mRNA levels of GR-alpha/beta, TNF-alpha, p105 and c-jun compared to controls. Compared to CS treatment, significantly increased mRNA levels were found for JNK1 under imipramine treatment and for GR-alpha after treatment with all AD examined. DISCUSSION: The multivariate approach meets the requirements of the complex situation of metabolic reactions induced by AD or CS treatment. Our data show that AD affect both, endocrine and signaling-related factors in human monocytic U-937 blood cells, although clearly not in a uniform manner. Hereby, GR is obviously playing a comparably central role. Overall, AD treatment might indeed normalize deviations of cellular endocrine and signaling-related pathways in major depressive disorder via the mechanisms examined.

Effects of antidepressants on mRNA levels of antioxidant enzymes in human monocytic U-937 cells.

Alterations of antioxidant enzyme activities have been described in a number of psychiatric disorders including major depression. Subsequently, the present study examined the effects of different types of antidepressants (desipramine, imipramine, maprotiline and mirtazapine) in different concentrations (10(-5), 10(-6) and 10(-7) M) on the mRNA levels of various enzymes of the antioxidant system, including both intracellular superoxide dismutase isoforms, glutathione peroxidase and catalase as well as several enzymes of the glutathione metabolism in monocytic U-937 cells after short- and long-term treatment (2.5 and 24 h) via RT-PCR. Results indicated mainly short-term decreases in the mRNA levels of antioxidant enzymes after treatment with these substances in all the concentrations used. In addition, after long-term treatment, significant increases in the mRNA levels were seen in the cases of Cu, Zn superoxide dismutase, gamma-glutamyl-cysteine synthetase, glutathione-S-transferase and glutathione reductase, including the impacts of all the antidepressants used in concentrations of 10(-6) M and 10(-7) M. Based on the large number of significant effects of all types of antidepressants tested on various antioxidant enzymes, we suggest that antioxidant enzymes may represent important targets in the course of antidepressive treatment.

Effects of haloperidol, clozapine and olanzapine on the survival of human neuronal and immune cells in vitro.

Cytotoxic effects on neuronal as well as on immune cells have been reported for both typical and atypical antipsychotic drugs. We evaluated the effects of different concentrations of a typical (haloperidol) and two atypical (clozapine, olanzapine) antipsychotics on the survival of human neuronal (SH-SY5Y cells) and immune cells (U937 cells) by determining the metabolic activity after 24 h of incubation by the modified tetrazolium method. The dopaminergic neuroblastoma SH-SY5Y and the lymphoma U-937 cell line are well established models for in vitro investigations. To further elucidate possible mechanisms of action we also determined the ATP content in the cultured cells. After experimental treatment, significant effects were detected by Kruskal Wallis test for all treatment conditions. Post-hoc tests (Dunn's method) showed that haloperidol and clozapine at the two highest concentrations (25 and 50 microg/ml) caused a significant decrease of metabolic activity in both cell systems, which was also detectable after treatment with clozapine at a concentration of 12.5 microg/ml in U937 cells. In contrast, olanzapine induced a significant increase in metabolic activity of SH-SY5Y cells at all concentrations except for the concentration of 3.1 microg/ml, whereas the metabolic activity in U937 cells was increased at concentrations of 1.6 and 6.25 microg/ml. For the determination of ATP content, the LD(50) values of the metabolic activity were used, except for olanzapine for which no distinct LD(50) value was available. Significant changes were detected for all treatments and post-hoc tests revealed that haloperidol caused a significant decrease compared to the control condition in both cell systems. These findings suggest that antipsychotic substances of different classes exert differential metabolic effects in both neuronal and immune cell systems.

Effects of oxidative challenge and calcium on ATP-levels in neuronal cells.

BACKGROUND: Neurocellular overload with hydrogen peroxide (H2O2) induces oxidative stress and may initiate a cascade of intracellular toxic events leading to energy failure, increased lipid peroxidation and subsequently cell death. Studies suggest that hippocampal neurons may be more vulnerable to oxidative stress than cortical cells pointing to a differential vulnerability of neuronal cells. Since disturbed ATP- and calcium (Ca2+)-metabolism may be involved in this process, we here evaluated the effects of H2O2-induced oxidative stress and the involvement of Ca2+-regulation on neuronal energy metabolism. METHODS: Using primary cortical and hippocampal neurons as well as immortalized hippocampal HT22 cells, we determined ATP-levels and accompanying cell death after oxidative challenge with H2O2. Additionally, the combined effects of H2O2 and alterations in Ca2+-concentrations were pharmacologically characterized in more detail. RESULTS: H2O2-incubation decreased ATP-levels in a dose- and time-dependent manner in all neuronal cell systems tested. Such effects were most pronounced in primary hippocampal neurons. In cortical cells, increased ATP-levels were notable under low H2O2-concentrations. A dose-dependent decrease in ATP-concentrations was observed after treatment with Ca2+, which was further enhanced by additional H2O2-challenge. CONCLUSIONS: Our data underline that both, H2O2- and Ca2+-treatment, are able to disturb intracellular energy metabolism. Out of the different systems studied, the ATP-decrease is most pronounced in hippocampal primary neurons, suggesting that this mechanism contributes to the selective neuronal vulnerability to oxidative stress in these neurons.