Cognitive deficits in first-degree relatives of bipolar patients: the use of homogeneous subgroups in the search of cognitive endophenotypes.

Previous studies have demonstrated impairments in attention, memory and executive functions in euthymic bipolar patients (BP) as well as their unaffected first-degree relatives, albeit in an attenuated form. Subsequently, cognitive deficits are discussed as a possible endophenotype of bipolar disorder. However, recent studies showed that only a subgroup of BP shows cognitive impairments. The aim of the present study was to investigate cognitive functioning in relatives compared to BP, to find out if the differentiation in a cognitive deficit vs. non-deficit subgroup is valid for relatives of BP, too. Therefore, the performance of 27 unaffected relatives of BP, 27 euthymic BP and 27 HC were compared using a neuropsychological test battery. The results showed that BP exhibited a reduced psychomotor speed and deficits in working memory compared to relatives and HC. Relatives performed significantly slower (psychomotor speed) as compared to HC (p = 0.024); performance in the other test measures lie between BP and HC. Furthermore, a detailed evaluation of the data indicated that only subgroups of BP and relatives exhibited cognitive impairments in the implemented tests. However, the deficit and non-deficit groups did not differ in sociodemographic and clinical variables from each other, possibly due to the small sample size. In conclusion, our results suggest that reduced psychomotor speed could serve as a potential endophenotype for bipolar disorder which should be investigated along the developmental trajectory of this disorder, also to examine whether abnormalities therein precede onset of the first mood episode. Furthermore, the division of relatives into subgroups aids in the identification of stable trait markers and high-risk bipolar groups and could enable early prevention strategies. As to that more research using distinct and homogeneous subgroups is necessary.

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

BACKGROUND: A 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. METHODS: We 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. RESULTS: In 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. CONCLUSION: The 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.

[Mental Disorder and Partnership: the Influence and Potential Burden of Affective Disorders on the Quality of Partnerships]. / Psychische Störung und Partnerschaft: Auswirkungen und Belastungen affektiver Störungen auf die Partnerschaft.

AIM: The aim of the present study was to explore the connection between affective disorders and various aspects of the quality of relationships and their impact on partnerships. METHODS: In a multi-centric study, we used questionnaires to compare three groups of couples: 23 patients suffering from major depression and their partners, 32 patients with a bipolar disorder and their partners, and 49 healthy couples serving as controls. RESULTS: Regardless of the type of affective disorders, stability of the relationship, felt happiness and other measures of quality of partnership were significantly impaired in couples with an affected partner. Partners of patients experience a higher emotional strain in every day life compared to healthy controls. There was a trend showing that bipolar disorder leads to a greater burden and a higher conflict potential than depression. DISCUSSION: The present study deals with stabile partnerships in daily life, including severely disabled patients needing in-patient treatment. Taking into account the health status of their partners, we discuss various aspects of happiness, conflict potentials as well as impact on the quality of relationships.

Electrophysiological evidence of a typical cognitive distortion in bipolar disorder.

Patients suffering from bipolar disorder often report negative thoughts and a bias towards negative environmental stimuli. Previous studies show that this mood-congruent attentional bias could mediated by dysfunctions in anterior limbic regions. The Error-Related Negativity (ERN), which originates in the anterior cingulate cortex (ACC), has been used to research this negativity bias in depressed patients, and could also help to better understand the underlying mechanisms causing the negativity bias in bipolar patients. In this study we investigated error processing in patients with bipolar disorder. Acute depressive bipolar patients (n = 20) and age-matched healthy controls (n = 20) underwent a modified Eriksen Flanker Task to assess test performance and two error-related event-related potentials (ERPs), i.e., the ERN and Error Positivity (Pe) were measured by EEG. Half of the patients were measured again in a euthymic state. We found similar ERN amplitudes in bipolar patients as compared to healthy controls, but significantly reduced Pe amplitudes. Moreover, acutely depressed bipolar patients displayed an ERN and Pe even if they responded accurately or too slow, which indicates that correct responses are processed in a way similar to wrong responses. This can be interpreted as a psychophysiological correlate of typical cognitive distortions in depression, i.e., an erroneous perception of personal failures. This biased error perception partially remained when patients were in a euthymic state. Together, our data indicate that aberrant error processing of bipolar patients may be regarded a trait marker possibly reflecting a risk factor for depressive relapses in bipolar disorder.

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.

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

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.

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.

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.