Caution should be advised when recommending increased use of ECT based on low-quality evidence.

On the basis of a meta-analysis that compared patients with unipolar depression against patients with bipolar depression who received electroconvulsive treatment (ECT), Bahji et al. (1) concluded that their findings supported increased utilization of ECT in patients with treatment-refractory bipolar depression and urged for more clinicians to use ECT in both unipolar and bipolar depression. However, due to several methodological limitations in their meta-analysis their recommendations do not seem supported by the evidence. This article is protected by copyright. All rights reserved.

A multisystem composite biomarker as a preliminary diagnostic test in bipolar disorder.

OBJECTIVE: Diagnosis and management of bipolar disorder (BD) are limited by the absence of available laboratory tests. We aimed to combine data from different molecular levels and tissues into a composite diagnostic and state biomarker. METHODS: Expression levels of 19 candidate genes in peripheral blood, plasma levels of BDNF, NT-3, IL-6 and IL-18, leukocyte counts, and urinary markers of oxidative damage to DNA and RNA were measured in 37 adult rapid-cycling patients with BD in different affective states during a 6- to 12-month period and in 40 age- and gender-matched healthy individuals in a longitudinal, repeated measures design comprising a total of 211 samples. A composite biomarker was constructed using data-driven variable selection. RESULTS: The composite biomarker discriminated between patients with BD and healthy control individuals with an area under the receiver operating characteristic curve (AUC) of 0.83 and a sensitivity of 73% and specificity of 71% corresponding with a moderately accurate test. Discrimination between manic and depressive states had a moderate accuracy, with an AUC of 0.82 and a sensitivity of 92% and a specificity of 40%. CONCLUSION: Combining individual biomarkers across tissues and molecular systems could be a promising avenue for research in biomarker models in BD.

Increased DNA and RNA damage by oxidation in patients with bipolar I disorder.

The mechanisms underlying bipolar disorder (BD) and the associated medical burden are unclear. Damage generated by oxidation of nucleosides may be implicated in BD pathophysiology; however, evidence from in vivo studies is limited and the extent of state-related alterations is unclear. This prospective study investigated for we believe the first time the damage generated by oxidation of DNA and RNA strictly in patients with type I BD in a manic or mixed state and subsequent episodes and remission compared with healthy control subjects. Urinary excretion of 8-oxo-deoxyguanosine (8-oxodG) and 8-oxo-guanosine (8-oxoGuo), valid markers of whole-body DNA and RNA damage by oxidation, respectively, was measured in 54 patients with BD I and in 35 healthy control subjects using a modified ultraperformance liquid chromatography and mass spectrometry assay. Repeated measurements were evaluated in various affective phases during a 6- to 12-month period and compared with repeated measurements in healthy control subjects. Independent of lifestyle and demographic variables, a 34% (P<0.0001) increase in RNA damage by oxidation across all affective states, including euthymia, was found in patients with BD I compared with healthy control subjects. Increases in DNA and RNA oxidation of 18% (P<0.0001) and 8% (P=0.02), respectively, were found in manic/hypomanic states compared with euthymia, and levels of 8-oxodG decreased 15% (P<0.0001) from a manic or mixed episode to remission. The results indicate a role for DNA and RNA damage by oxidation in BD pathophysiology and a potential for urinary 8-oxodG and 8-oxoGuo to function as biological markers of diagnosis, state and treatment response in BD.

Peripheral blood brain-derived neurotrophic factor in bipolar disorder: a comprehensive systematic review and meta-analysis.

Peripheral blood brain-derived neurotrophic factor (BDNF) has been proposed as a potential biomarker related to disease activity and neuroprogression in bipolar disorder, speculated to mirror alterations in brain expression of BDNF. The research area is rapidly evolving; however, recent investigations have yielded conflicting results with substantial variation in outcomes, highlighting the need to critically assess the state of current evidence. The aims of the study were to investigate differences in peripheral blood BDNF concentrations between bipolar disorder patients and healthy control subjects and between affective states in bipolar disorder patients, including assessment of the effect of treatment of acute episodes on BDNF levels. A systematic review of English language studies without considering publication status was conducted in PubMed (January 1950-November 2014), Embase (1974-November 2014) and PsycINFO (1806-November 2014), and 35 studies comprising a total of 3798 participants were included in the meta-analysis. The results indicated that crude peripheral blood BDNF levels may be lower in bipolar disorder patients overall (Hedges' g=-0.28, 95% CI: -0.51 to -0.04, P=0.02) and in serum of manic (g=-0.77, 95% CI: -1.36 to -0.18, P=0.01) and depressed (g=-0.87, 95% CI: -1.42 to -0.32, P=0.002) bipolar disorder patients compared with healthy control subjects. No differences in peripheral BDNF levels were observed between affective states overall. Longer illness duration was associated with higher BDNF levels in bipolar disorder patients. Relatively low study quality, substantial unexplained between-study heterogeneity, potential bias in individual studies and indications of publication bias, was observed and studies were overall underpowered. It could thus not be excluded that identified differences between groups were due to factors not related to bipolar disorder. In conclusion, limitations in the evidence base prompt tempered conclusions regarding the role of peripheral BDNF as a biomarker in bipolar disorder and substantially improving the quality of further research is warranted.

A composite peripheral blood gene expression measure as a potential diagnostic biomarker in bipolar disorder.

Gene expression in peripheral blood has the potential to inform on pathophysiological mechanisms and has emerged as a viable avenue for the identification of biomarkers. Here, we aimed to identify gene expression candidate genes and to explore the potential for a composite gene expression measure as a diagnostic and state biomarker in bipolar disorder. First, messenger RNA levels of 19 candidate genes were assessed in peripheral blood mononuclear cells of 37 rapid cycling bipolar disorder patients in different affective states (depression, mania and euthymia) during a 6-12-month period and in 40 age- and gender-matched healthy control subjects. Second, a composite gene expression measure was constructed in the first half study sample and independently validated in the second half of the sample. We found downregulation of POLG and OGG1 expression in bipolar disorder patients compared with healthy control subjects. In patients with bipolar disorder, upregulation of NDUFV2 was observed in a depressed state compared with a euthymic state. The composite gene expression measure for discrimination between patients and healthy control subjects on the basis of 19 genes generated an area under the receiver-operating characteristic curve of 0.81 (P < 0.0001) in sample 1, which was replicated with a value of 0.73 (P < 0.0001) in sample 2, corresponding with a moderately accurate test. The present findings of altered POLG, OGG1 and NDUFV2 expression point to disturbances within mitochondrial function and DNA repair mechanisms in bipolar disorder. Further, a composite gene expression measure could hold promise as a potential diagnostic biomarker.

Oxidation of plasma low-density lipoprotein accelerates its accumulation and degradation in the arterial wall in vivo.

BACKGROUND: The aim of the present study was to investigate whether oxidized LDL (ox-LDL) in the arterial intima could be derived from LDL already oxidized in plasma. METHODS AND RESULTS: Rabbits received an intravenous injection of 125I-labeled normal LDL (N-LDL) mixed with 131I-labeled LDL that had been mildly oxidized through exposure to Cu2+. The aortic accumulation of undegraded labeled LDL was expressed as plasma equivalents and cakulated as radioactivity in the intima/inner media (cpm/cm2) divided by the time-averaged concentration of radioactivity in plasma (cpm/nL): for the thoracic aorta, the accumulation of undegraded ox-LDL in the intima/ inner media exceeded that of undegraded N-LDL by 286% (n = 6, P < .04), 863% (n = 7, P < .02), and 364% (n = 8, P < .01) after 1, 3, and 24 hours of exposure, respectively. There was a strong positive association between the extent of oxidation and the excess accumulation of undegraded ox-LDL compared with N-LDL (thoracic aorta; 3 hours of exposure: r = .97, n = 14, P < .00001). To measure degradation of N-LDL and ox-LDL, 125I-LDL labeled with 131I-tyramine cellobiose was injected intravenously 24 hours before the aortic intima/inner media was removed: for the thoracic aorta, the accumulation of degradation products from ox-LDL (n = 6) exceeded that from N-LDL (n = 6) by 301% (P < .04). CONCLUSIONS: The present data suggest a novel mechanism: mildly oxidized LDL may circulate in plasma for a period sufficiently long to enter, accumulate, and be degraded in the arterial intima in preference to N-LDL.