Julia Volkert

Cross-disorder analysis of bipolar risk genes: further evidence of DGKH as a risk gene for bipolar disorder, but also unipolar depression and adult ADHD.

Recently, several genome-wide association studies (GWAS) on bipolar disorder (BPD) suggested novel risk genes. However, only few of them were followed up and further, the specificity of these genes is even more elusive. To address these issues, we genotyped SNPs in ANK3, CACNA1C, CMTM8, DGKH, EGFR, and NPAS3, which were significantly associated with BPD in previous GWAS, in a sample of 380 BPD patients. Replicated SNPs were then followed up in patients suffering from unipolar depression (UPD; n=387) or adult attention-deficit/hyperactivity disorder (aADHD; n=535). While we could not confirm an association of ANK3, CACNA1C, and EGFR with BPD, 10 SNPs in DGKH, CMTM8, and NPAS3 were nominally associated with disease, with two DGKH markers surviving correction for multiple testing. When these were followed up in UPD and aADHD, seven DGKH SNPs were also associated with UPD, while one SNP each in NPAS3 and CMTM8 and four in DGKH were linked to aADHD. Furthermore, a DGKH haplotype consisting of rs994856/rs9525580/rs9525584 GAT was associated with all disorders tested, while the complementary AGC haplotype was protective. The corresponding haploblock spans a 27-kb region covering exons coding for amino acids 65–243, and thus might include functional variants yet to be identified. We demonstrate an association of DGKH with BPD, UPD, and aADHD by applying a two-stage design. These disorders share the feature of mood instability, so that this phenotype might be associated with genetic variation in DGKH.

The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia : further evidence and meta-analysis

NO is a pleiotropic signaling molecule and has an important role in cognition and emotion. In the brain, NO is produced by neuronal nitric oxide synthase (NOS-I, encoded by NOS1) coupled to the NMDA receptor via PDZ interactions; this protein-protein interaction is disrupted upon binding of NOS1 adapter protein (encoded by NOS1AP) to NOS-I. As both NOS1 and NOS1AP were associated with schizophrenia, we here investigated these genes in greater detail by genotyping new samples and conducting a meta-analysis of our own and published data. In doing so, we confirmed association of both genes with schizophrenia and found evidence for their interaction in increasing risk towards disease. Our strongest finding was the NOS1 promoter SNP rs41279104, yielding an odds ratio of 1.29 in the meta-analysis. As findings from heterologous cell systems have suggested that the risk allele decreases gene expression, we studied the effect of the variant on NOS1 expression in human post-mortem brain samples and found that the risk allele significantly decreases expression of NOS1 in the prefrontal cortex. Bioinformatic analyses suggest that this might be due the replacement of six transcription factor binding sites by two new binding sites as a consequence of proxy SNPs. Taken together, our data argue that genetic variance in NOS1 resulting in lower prefrontal brain expression of this gene contributes to schizophrenia liability, and that NOS1 interacts with NOS1AP in doing so. The NOS1-NOS1AP PDZ interface may thus well constitute a novel target for small molecules in at least some forms of schizophrenia.

Further evidence for plasma progranulin as a biomarker in bipolar disorder

BACKGROUND A recent study suggested that progranulin (encoded by the fronto-temporal dementia risk gene GRN) plasma levels are decreased in bipolar disorder (BD). Replication of this finding is however lacking. METHODS Progranulin plasma levels of bipolar patients (n=104) and healthy controls (n=80) were measured by enzyme-linked immunosorbent assay (ELISA). Participants were also genotyped for three single nucleotide polymorphisms (SNPs) in the GRN gene (rs2879096, rs4792938 and rs5848), and the effect of genetic variation on progranulin levels was examined. RESULTS Plasma progranulin levels were decreased in BD (ANCOVA, p=0.001). Furthermore, age was significantly and positively correlated with plasma progranulin (Pearson׳s correlation, r=0.269, p<0.001). Also, lithium treatment but no other medication had a significant effect on progranulin plasma levels (ANCOVA, p=0.007). Specifically in BD, the GRN SNP rs5848 was associated with progranulin plasma levels (Kruskal-Wallis test, p<0.005). LIMITATIONS Subgroup analysis regarding bipolar I vs. bipolar II subtype and polarity of the episode at sampling (manic vs. depressed vs. mixed vs. rapid cycling vs. euthymic) could only be performed with limited validity due to the relatively small sample size. The suitability of peripheral progranulin as a biomarker for BD is limited due to the overlap between patients and controls. CONCLUSION The findings strengthen the evidence for progranulin being involved in pathomechanisms of bipolar disorder, and suggest a genetic determinant of progranulin concentrations that is relevant specifically in bipolar patients.

Internet use by patients with bipolar disorder:results from an international multisite survey

There is considerable international interest in online education of patients with bipolar disorder, yet little understanding of how patients use the Internet and other sources to seek information. 1171 patients with a diagnosis of bipolar disorder in 17 countries completed a paper-based, anonymous survey. 81% of the patients used the Internet, a percentage similar to the general public. Older age, less education, and challenges in country telecommunications infrastructure and demographics decreased the odds of using the Internet. About 78% of the Internet users looked online for information on bipolar disorder or 63% of the total sample. More years of education in relation to the country mean, and feeling very confident about managing life decreased the odds of seeking information on bipolar disorder online, while having attended support groups increased the odds. Patients who looked online for information on bipolar disorder consulted medical professionals plus a mean of 2.3 other information sources such as books, physician handouts, and others with bipolar disorder. Patients not using the Internet consulted medical professionals plus a mean of 1.6 other information sources. The percentage of patients with bipolar disorder who use the Internet is about the same as the general public. Other information sources remain important.

Multi-level biomarker analysis of nitric oxide synthase isoforms in bipolar disorder and adult ADHD

Introduction: Several studies have shown altered levels of nitric oxide (NO) and its stable metabolites (NOx-) in blood and cerebrospinal fluid of psychiatric patients. The aim of our study was to replicate previous findings and investigate the influence of the nitrinergic system in bipolar disorder and adult attention-deficit/hyperactivity disorder (aADHD) in particular. Methods: The concentrations of NO2- and NO3- in peripheral blood in a sample of aADHD, bipolar disorder (BPD) and controls were analysed. The sample was genotyped for a three marker haplotype in the NOS3 gene (rs2070744, rs1799983 and Intron 4 VNTR) and for genetic variants of the NOS1 gene (NOS1 ex 1c, NOS1 ex 1f). Finally, qRT PCR was performed. Results: We found significantly lower NOx- levels in BPD (p<0.001). rs2070744 T/T-carriers of the whole sample showed increased mRNA expression of NOS3 (p=0.05). Only in BPD an influence of rs2070744 was seen regarding NO metabolite levels; C/C carriers displayed lower NOx- levels (p=0.05). Conclusion: We could replicate and extend previous findings showing altered NOx- levels in BPD and an influence of NOS3 rs2070744 on NOS3 expression and NOx- concentration. Together, these data point to a role of the nitrinergic pathway in BPD.

Predominant polarity in bipolar disorder and validation of the polarity index in a German sample

BackgroundA large number of patients with bipolar disorder (BD) can be characterized by predominant polarity (PP), which has important implications for relapse prevention. Recently, Popovic et al. (EUR NEUROPSYCHOPHARM 22(5): 339-346, 2012) proposed the Polarity Index (PI) as a helpful tool in the maintenance treatment of BD. As a numeric expression, it reflects the efficacy of drugs used in treatment of BD. In the present retrospective study, we aimed to validate this Index in a large and well characterized German bipolar sample.MethodsWe investigated 336 bipolar patients (BP) according to their PP and calculated the PI for each patient in order to prove if maintenance treatment differs according to their PP. Furthermore, we analysed whether PP is associated with demographic and clinical characteristics of BP.ResultsIn our sample, 63.9% of patients fulfilled criteria of PP: 169 patients were classified as depressive predominant polarity (DPP), 46 patients as manic predominant polarity (MPP). The two groups differed significantly in their drug regime: Patients with DPP were more often medicated with lamotrigine and antidepressants, patients with MPP were more often treated with lithium, valproate, carbamazepine and first generation antipsychotics. However, patients with DPP and MPP did not differ significantly with respect to the PI, although they received evidence-based and guideline-driven treatment.ConclusionThe reason for this negative finding might well be that for several drugs, which were used frequently, no PI value is available. Nevertheless we suggest PP as an important concept in the planning of BD maintenance treatment.

A preliminary study on methylphenidate-regulated gene expression in lymphoblastoid cells of ADHD patients

Abstract Objectives. Methylphenidate (MPH) is a commonly used stimulant medication for treating attention-deficit/hyperactivity disorder (ADHD). Besides inhibiting monoamine reuptake there is evidence that MPH also influences gene expression directly. Methods. We investigated the impact of MPH treatment on gene expression levels of lymphoblastoid cells derived from adult ADHD patients and healthy controls by hypothesis-free, genome-wide microarray analysis. Significant findings were subsequently confirmed by quantitative Real-Time PCR (qRT PCR) analysis. Results. The microarray analysis from pooled samples after correction for multiple testing revealed 138 genes to be marginally significantly regulated due to MPH treatment, and one gene due to diagnosis. By qRT PCR we could confirm that GUCY1B3 expression was differential due to diagnosis. We verified chronic MPH treatment effects on the expression of ATXN1, HEY1, MAP3K8 and GLUT3 in controls as well as acute treatment effects on the expression of NAV2 and ATXN1 specifically in ADHD patients. Conclusions. Our preliminary results demonstrate MPH treatment differences in ADHD patients and healthy controls in a peripheral primary cell model. Our results need to be replicated in larger samples and also using patient-derived neuronal cell models to validate the contribution of those genes to the pathophysiology of ADHD and mode of action of MPH.

International multi-site survey on the use of online support groups in bipolar disorder

Abstract Background: Peer support is an established component of recovery from bipolar disorder, and online support groups may offer opportunities to expand the use of peer support at the patient’s convenience. Prior research in bipolar disorder has reported value from online support groups. Aims: To understand the use of online support groups by patients with bipolar disorder as part of a larger project about information seeking. Methods: The results are based on a one-time, paper-based anonymous survey about information seeking by patients with bipolar disorder, which was translated into 12 languages. The survey was completed between March 2014 and January 2016 and included questions on the use of online support groups. All patients were diagnosed by a psychiatrist. Analysis included descriptive statistics and general estimating equations to account for correlated data. Results and conclusions: The survey was completed by 1222 patients in 17 countries. The patients used the Internet at a percentage similar to the general public. Of the Internet users who looked online for information about bipolar disorder, only 21.0% read or participated in support groups, chats, or forums for bipolar disorder (12.8% of the total sample). Given the benefits reported in prior research, clarification of the role of online support groups in bipolar disorder is needed. With only a minority of patients using online support groups, there are analytical challenges for future studies.

Erratum to: Online information seeking by patients with bipolar disorder: results from an international multisite survey (Int J Bipolar Disord, (2016), 4, (1), 10.1186/s40345-016-0058-0)

Online information seeking by patients with bipolar disorder: results from an international multisite survey (Int J Bipolar Disord, (2016), 4, (1), 10.1186/s40345-0160058-0) Conell, Jörn; Bauer, Rita; Glenn, Tasha; Alda, Martin; Ardau, Raffaella; Baune, Bernhard T.; Berk, Michael; Bersudsky, Yuly; Bilderbeck, Amy; Bocchetta, Alberto; Bossini, Letizia; Paredes Castro, Angela Marianne; Cheung, Eric Yat Wo; Chillotti, Caterina; Choppin, Sabine; Del Zompo, Maria; Dias, Rodrigo; Dodd, Seetal; Duffy, Anne; Etain, Bruno; Fagiolini, Andrea; Garnham, Julie; Geddes, John; Gildebro, Jonas; Gonzalez-Pinto, Ana; Goodwin, Guy M.; Grof, Paul; Harima, Hirohiko; Hassel, Stefanie; Henry, Chantal; Hidalgo-Mazzei, Diego; Kapur, Vaisnvy; Kunigiri, Girish; Lafer, Beny; Lam, Chun; Larsen, Erik Roj; Lewitzka, Ute; Licht, Rasmus W.; Lund, Anne Hvenegaard; Misiak, Blazej; Piotrowski, Patryk; Monteith, Scott; Munoz, Rodrigo; Nakanotani, Takako; Nielsen, René E.; O’Donovan, Claire; Okamura, Yasushi; Osher, Yamima; Reif, Andreas; Ritter, Philipp; Rybakowski, Janusz K.; Sagduyu, Kemal; Sawchuk, Brett; Schwartz, Elon; Scippa, Ângela Miranda; Slaney, Claire; Sulaiman, Ahmad Hatim; Suominen, Kirsi; Suwalska, Aleksandra; Tam, Peter; Tatebayashi, Yoshitaka; Tondo, Leonardo; Vieta, Eduard; Vinberg, Maj; Viswanath, Biju; Volkert, Julia; Zetin, Mark; Zorrilla, Iñaki; Whybrow, Peter C.; Bauer, Michael

EPA-1495 – Evidence for cognitive subgroups in bipolar disorder and the influence of subclinical depression

Recent research in bipolar disorder points at the relevance and persistence of cognitive deficits in bipolar patients (BPD) even beyond acute episodes of depression or mania. Impairments were found in attention, processing speed, memory and executive functioning. Up to now, the mechanisms, why some BPD do not reach their former level of cognitive performance and psychosocial functioning, while others are remitted completely, is not understood. In this study we aimed to identify a’deficit vs. nondeficit subgroup’ within BPD. For this purpose, we investigated the association between demographic and disease specific variables and the cognitive performance of BPD. The test performance of 70 remitted outpatients (Bipolar-Type I and II) was compared to 70 healthy controls (HC). Participants performed an extensive neuropsychological test battery. As expected our sample of euthymic BPD performed significantly worse than HCs in three of eight cognitive domains, namely Planning, Cognitive Flexibility and Divided Attention. In line with previous findings, more than a half of the euthymic BPD did not have any neuropsychological deficits. We found no significant correlations between test performance and clinical variables. But interestingly, we revealed significant associations between subthreshold depressive symptomatology and psychomotor slowing, impaired long term and working memory. In sum, these results suggest the presence of cognitive subgroups in bipolar disorder. However, we found no evidence of underlying etiologies: Clinical characteristics seem to have no influence. However, our results indicate that cognitive deficits found in euthymic BPD could result from a subdepressive syndrome and not per se by disease characteristics.