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Introduction: Distinguishing those with a personality disorder from those with major depressive disorder (MDD) can be challenging, but establishing the correct diagnosis can direct appropriate management., Aim: To identify whether behavioural themes differ between those with personality disorders from those with MDD, and how those differences might relate to a clinical team's perception of diagnosis., Method: An observational study identifying all inpatients presenting with symptoms of depression. At discharge, patients (n = 60) underwent a structured diagnostic interview and were grouped according to diagnosis. Qualitative data was analysed to determine whether behavioural themes differed between those with MDD and those with a personality disorder (with or without MDD)., Results: Ward staff perceptions of diagnosis aligned in all cases of personality disorder, but they also attributed that diagnosis to 54% of patients who had only MDD. Several behavioural themes were evident in those with a personality disorder but not those with MDD. Many behavioural themes were observed in both groups, and it is likely these that drove differences in diagnostic views., Implications for Practice: Certain behavioural themes may be determinants of the perception of diagnosis held by inpatient staff, and when present in acute episodes in MDD, may risk diagnostic misattribution., (© 2024 John Wiley & Sons Ltd.)

Background: People with bipolar disorder (BD) tend to show widespread cognitive impairment compared to healthy controls. Impairments in processing speed (PS), attention and executive function (EF) may represent 'core' impairments that have a role in wider cognitive dysfunction. Cognitive impairments appear to relate to structural brain abnormalities in BD, but whether core deficits are related to particular brain regions is unclear and much of the research on brain-cognition associations is limited by univariate analysis and small samples., Methods: Euthymic BD patients (n = 56) and matched healthy controls (n = 26) underwent T1-weighted MRI scans and completed neuropsychological tests of PS, attention and EF. We utilised public datasets to develop normative models of cortical thickness (n = 5977) to generate robust estimations of cortical abnormalities in patients. Canonical correlation analysis was used to assess multivariate brain-cognition associations in BD, controlling for age, sex and premorbid IQ., Results: BD showed impairments on tests of PS, attention and EF, and abnormal cortical thickness in several brain regions compared to healthy controls. Impairments in tests of PS and EF were most strongly associated with cortical thickness in the left inferior temporal, right entorhinal and right temporal pole areas., Conclusion: Impairments in PS, attention and EF can be observed in euthymic BD and may be related to abnormal cortical thickness in temporal regions. Future research should continue to leverage normative modelling and multivariate methods to examine complex brain-cognition associations in BD. Future research may benefit from exploring covariance between traditional brain structural morphological metrics such as cortical thickness, cortical volume and surface area., (© 2024 The Author(s). Bipolar Disorders published by John Wiley & Sons Ltd.)

Background: Lithium is an effective mood stabiliser, but its mechanism of action is incompletely defined. Even at very low doses, lithium may have neuroprotective effects, but it is not clear if these relate to brain lithium concentration in vivo. We have developed magnetic resonance imaging ( 7 Li-MRI) methods to detect lithium in the brain following supplementation at a very low dose., Methods: Lithium orotate supplements were taken by nine healthy adult male subjects (5 mg daily) for up to 28 days, providing 2-7 % of the lithium content of a typical therapeutic lithium carbonate dose. One-dimensional 7 Li-images were acquired on a 3.0 T MRI scanner. All subjects were scanned on day 14 or 28; seven were scanned on both, one at baseline and one after 7-days washout., Results: 7 Li-MR signal amplitude was broadly stable between days 14 and 28. Two subjects had notably higher 7 Li-signal intensities (approximately 2-4×) compared to other study participants., Limitations: Lithium adherence was self-reported by all participants without formal validation. The coarse spatial resolution necessary for detection of low concentrations of 7 Li exhibits imperfect spatial separation of signal from adjacent pixels., Conclusions: 7 Li-MRI performed using a clinical 3T scanner demonstrated detection of lithium in the brain at very low concentration, in the range of approximately 10-60 mM. The methods are suited to studies assessing low dose lithium administration in psychiatric and neurodegenerative disorders, and permit the comparison of different lithium salt preparations at a time of emerging interest in the field., Competing Interests: Declaration of competing interest RS declares honoraria from Janssen (unrelated to this work). All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Since 1968, the Australian Dung Beetle Project has carried out field releases of 43 deliberately introduced dung beetle species for the biological control of livestock dung and dung-breeding pests. Of these, 23 species are known to have become established. For most of these species, sufficient time has elapsed for population expansion to fill the extent of their potential geographic range through both natural and human-assisted dispersal. Consequently, over the last 20 years, extensive efforts have been made to quantify the current distribution of these introduced dung beetles, as well as the seasonal and spatial variation in their activity levels. Much of these data and their associated metadata have remained unpublished, and they have not previously been synthesized into a cohesive dataset. Here, we collate and report data from the three largest dung beetle monitoring projects from 2001 to 2022. Together, these projects encompass data collected from across Australia, and include records for all 23 species of established dung beetles introduced for biocontrol purposes. In total, these data include 22,718 presence records and 213,538 absence records collected during 10,272 sampling events at 546 locations. Most presence records (97%) include abundance data. In total, 1,752,807 dung beetles were identified as part of these data. The distributional occurrence and abundance data can be used to explore questions such as factors influencing dung beetle species distributions, dung beetle biocontrol, and insect-mediated ecosystem services. These data are provided under a CC-BY-NC 4.0 license and users are encouraged to cite this data paper when using the data., (© 2024 The Authors. Ecology published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)

Normative models of brain structure estimate the effects of covariates such as age and sex using large samples of healthy controls. These models can then be applied to smaller clinical cohorts to distinguish disease effects from other covariates. However, these advanced statistical modelling approaches can be difficult to access, and processing large healthy cohorts is computationally demanding. Thus, accessible platforms with pre-trained normative models are needed. We present such a platform for brain morphology analysis as an open-source web application https://cnnplab.shinyapps.io/normativemodelshiny/, with six key features: (i) user-friendly web interface, (ii) individual and group outputs, (iii) multi-site analysis, (iv) regional and whole-brain analysis, (v) integration with existing tools, and (vi) featuring multiple morphology metrics. Using a diverse sample of 3,276 healthy controls across 21 sites, we pre-trained normative models on various metrics. We validated the models with a small clinical sample of individuals with bipolar disorder, showing outputs that aligned closely with existing literature only after applying our normative modelling. Further validation with a cohort of temporal lobe epilepsy showed agreement with previous group-level findings and individual-level seizure lateralisation. Finally, with the ability to investigate multiple morphology measures in the same framework, we found that biological covariates are better explained in specific morphology measures, and for clinical applications, only some measures are sensitive to the disease process. Our platform offers a comprehensive framework to analyse brain morphology in clinical and research settings. Validations confirm the superiority of normative models and the advantage of investigating a range of brain morphology metrics together.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD., (© 2024. The Author(s).)

Background: The relationship between major depressive disorder (MDD) and personality disorders is complex, with implications for diagnosis and treatment. We sought to explore the relationship between these disorders quantitatively in an inpatient setting., Methods: We conducted a structured observational study exploring symptoms of depression and selected neurocognitive functions over the span of an inpatient admission in those with depression and personality disorders. Sixty inpatients presenting with symptoms of depression completed ratings of mood and neurocognitive function. Diagnosis was confirmed by structured clinical interview (SCID-5-RV) at discharge and used to allocate patients to one of the two groups for analysis: those with MDD-only and those with a personality disorder (with or without MDD)., Results: On admission, observer-based ratings of depression were significantly higher in the MDD-only group while subjective ratings were higher in the personality disorder group. Depression rating scores lessened in both groups during the admission, but at discharge, the personality disorder group continued to report higher subjective ratings. The personality disorder group also rated themselves as more cognitively impaired than the MDD-only group and unlike the MDD-only group, they did not report subjective improvements in cognitive function over the course of admission. Objective assessment of cognitive function demonstrated improvements in both groups., Conclusions: In this study, the presence of a personality disorder was associated with greater subjective severity of depressive symptomatology and selected neurocognitive functioning, despite similar or lower objective severity in comparison with those with MDD. This finding has implications for understanding the patient journey through health care settings.

Aims and Method: A supply disruption alert in 2020, now rescinded, notified UK prescribers of the planned discontinuation of Priadel ® (lithium carbonate) tablets. This service evaluation explored lithium dose and plasma levels before and after the switching of lithium brands, in order to determine the interchangeability of different brands of lithium from a pharmacokinetic perspective., Results: Data on the treatment of 37 patients switched from Priadel ® tablets were analysed. Switching to Camcolit ® controlled-release tablets at the same dose did not result in meaningful differences in plasma lithium levels. Dose adjustment and known or suspected poor medication adherence were associated with greater variability in plasma lithium levels on switching brands., Clinical Implications: For comparable pre- and post-switch doses in adherent patients, the most common brands of lithium carbonate appear to produce similar plasma lithium levels. British National Formulary guidance relating to switching lithium brands may be unnecessarily complex.

Background: Lithium is widely evidenced for its neuropsychiatric benefits. Advantages of 'sub-therapeutic' doses are increasingly being reported, which is apposite given enduring concerns around adverse effects of 'therapeutic' doses. We aimed to synthesise all available evidence from interventional studies investigating low-dose lithium (LDL) across neuropsychiatric outcomes., Methods: Electronic databases were systematically searched to include studies where a group of adult humans were treated with LDL (∼serum level ≤0.6 mmol/L), where data describing a neuropsychiatric outcome were reported either before and after treatment, and/or between lithium and a comparator., Results: 18 articles were examined and grouped according to outcome domain (cognition, depression, mania, and related constructs e.g., suicidality). Significant benefits (versus placebo) were identified for attenuating cognitive decline, and potentially as an adjunctive therapy for people with depression/mania. Across studies, LDL was reported to be safe., Conclusions: Despite the paucity and heterogeneity of studies, LDL's apparent pro-cognitive effects and positive safety profile open promising avenues in the fields of neurodegeneration, and augmentation in affective disorders. We urge future examinations of LDL's potential to prevent cognitive/affective syndromes., Competing Interests: Competing interests In the last 36 months: RS declares an honorarium from Janssen. AHY declares honoraria for speaking from Astra Zeneca, Lundbeck, Eli Lilly, Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion, Janssen; and research grant support from Janssen. JK owns shares in AstraZeneca and GSK plc. MFJ declares honoraria for speaking from Janssen, Lundbeck, EMS and Daiichi Sankyo; honoraria for consulting from Janssen and Lundbeck; and research grant support from Lundbeck and Heptares Therapeutics. Other authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Lithium is one of the most effective medications for bipolar disorder episode prevention, but its mechanism of action is still largely unknown. The hippocampus is a subcortical cerebral structure involved in the formation of emotional responses, cognition and various primitive functions, altered during affective episodes. Deviations in the anatomy or physiology of the hippocampus would partially explain the symptomatology of bipolar subjects, and restoration may reflect treatment response., Methods: In this mini review, we summarize the studies which have investigated the effect of lithium intake on the volume of hippocampus, measured using magnetic resonance imaging (MRI). We performed a bibliographic search on PubMed, using the terms terms "hippocampus", "lithium", "bipolar disorder", "volume" and "MRI". Only original studies were considered., Results: Thirteen studies met the inclusion criteria. Nine studies demonstrated increased total hippocampal volume or hippocampal subfield volumes in BD patients on lithium treatment (Li BD) compared to those not taking lithium (non-Li BD), while four failed to show significant differences between groups. When healthy controls were compared to either the Li subjects or the non-Li ones, the findings were more heterogeneous., Limitations: Heterogeneity in the methodology and definition of groups limits the comparison of study results., Conclusions: Lithium may be associated with increased hippocampal volume in BD, potentially due to its putative neurotrophic action, but further research is needed better define the morphological alterations of hippocampus in BD and the longitudinal effects of lithium in the short and long-term., (Copyright © 2021. Published by Elsevier B.V.)

Background: Proton longitudinal relaxation (T 1 ) is a quantitative MRI-derived tissue parameter sensitive to myelin, macromolecular, iron and water content. There is some evidence to suggest that cortical T 1 is elevated in bipolar disorder and that lithium administration reduces cortical T 1 . However, T 1 has not yet been quantified in separate groups containing lithium-treated patients, lithium-naïve patients, and matched healthy controls., Methods: Euthymic patients with bipolar disorder receiving lithium (n = 18, BDL) and those on other medications but naïve to lithium (n = 20, BDC) underwent quantitative T 1 mapping alongside healthy controls (n = 18, HC). T 1 was compared between groups within the cortex, white matter and subcortical structures using regions of interest (ROI) derived from the Desikan-Killiany atlas. Effect sizes for each ROI were computed for BDC vs BDL groups and Bipolar Disorder vs HC groups., Results: No significant differences in T 1 were identified between BDL and BDC groups when corrected for multiple comparisons. Patients with bipolar disorder had significantly higher mean T 1 in a range of ROIs compared to healthy controls, including bilateral motor, somatosensory and superior temporal regions, subcortical structures and white matter., Conclusions: The higher T 1 values observed in the patients with bipolar disorder may reflect abnormal tissue microstructure. Whilst the precise mechanism remains unknown, these findings may have a basis in differences in myelination, macromolecular content, iron and water content between patients and controls., (© 2019 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Background: Vagus nerve stimulation (VNS) has been shown to improve long-term outcomes for some patients with difficult-to-treat depression (DTD)., Objectives: Set out criteria to support the identification of patients for whom VNS is a suitable treatment option., Methods: Published clinical evidence, coupled with clinical experience garnered at the Regional Affective Disorders Service (RADS; Newcastle, UK) to inform VNS criteria., Results: Patients with major depressive disorder or bipolar disorder (predominantly depressive) and a history of failed trials of multiple treatment modalities including pharmacotherapy, psychotherapy and/or electroconvulsive therapy (ECT) may be suitable candidates for VNS, if no contraindications are present. In the RADS such patients are offered VNS if they are able to provide informed consent and two specialists agree it is appropriate., Conclusions: VNS provides a valuable treatment option for DTD when used under appropriate circumstances; these assessment criteria facilitate the identification of patients with greatest potential to benefit., (Copyright © 2020. Published by Elsevier B.V.)

Background: Lithium is recommended as a first line treatment for bipolar disorders. However, only 30% of patients show an optimal outcome and variability in lithium response and tolerability is poorly understood. It remains difficult for clinicians to reliably predict which patients will benefit without recourse to a lengthy treatment trial. Greater precision in the early identification of individuals who are likely to respond to lithium is a significant unmet clinical need., Structure: The H2020-funded Response to Lithium Network (R-LiNK; http://www.r-link.eu.com/ ) will undertake a prospective cohort study of over 300 individuals with bipolar-I-disorder who have agreed to commence a trial of lithium treatment following a recommendation by their treating clinician. The study aims to examine the early prediction of lithium response, non-response and tolerability by combining systematic clinical syndrome subtyping with examination of multi-modal biomarkers (or biosignatures), including omics, neuroimaging, and actigraphy, etc. Individuals will be followed up for 24 months and an independent panel will assess and classify each participants' response to lithium according to predefined criteria that consider evidence of relapse, recurrence, remission, changes in illness activity or treatment failure (e.g. stopping lithium; new prescriptions of other mood stabilizers) and exposure to lithium. Novel elements of this study include the recruitment of a large, multinational, clinically representative sample specifically for the purpose of studying candidate biomarkers and biosignatures; the application of lithium-7 magnetic resonance imaging to explore the distribution of lithium in the brain; development of a digital phenotype (using actigraphy and ecological momentary assessment) to monitor daily variability in symptoms; and economic modelling of the cost-effectiveness of introducing biomarker tests for the customisation of lithium treatment into clinical practice. Also, study participants with sub-optimal medication adherence will be offered brief interventions (which can be delivered via a clinician or smartphone app) to enhance treatment engagement and to minimize confounding of lithium non-response with non-adherence., Conclusions: The paper outlines the rationale, design and methodology of the first study being undertaken by the newly established R-LiNK collaboration and describes how the project may help to refine the clinical response phenotype and could translate into the personalization of lithium treatment.

Background: Lithium treatment is associated with an increase in magnetic resonance imaging derived measures of white matter integrity, but the relationship between the spatial distribution of brain lithium and white matter integrity is unknown., Methods: Euthymic patients with bipolar disorder receiving lithium (n = 12) and those on other medications but naïve to lithium (n = 17) underwent diffusion imaging alongside matched healthy controls (n = 16). Generalised fractional anisotropy (gFA) within white matter was compared between groups using a standard space white matter atlas. Lithium-treated patients underwent novel multinuclear lithium magnetic resonance imaging ( 7 Li-MRI) to determine the relative lithium concentration across the brain. The relationship between 7 Li-MRI signal intensity and gFA was investigated at the resolution of the 7 Li-MRI sequence in native space., Results: Lithium-treated bipolar disorder and healthy control groups had higher mean white matter gFA than the bipolar disorder group treated with other medications (t = 2.5, p < 0.05; t = 2.7, p < 0.03, respectively). No differences in gFA were found between patients taking lithium and healthy controls (t = 0.02, p = 1). These effects were seen consistently across most regions in the white matter atlas. In the lithium-treated group, a significant effect of the 7 Li-MRI signal in predicting the gFA (p < 0.01) was identified in voxels containing over 50% white matter., Limitations: Cross-sectional evaluation of a relatively small cohort., Conclusions: The higher gFA values observed in the lithium-treated bipolar disorder group suggests that long-term lithium is associated with greater white matter integrity. Our novel analysis supports this further, showing a positive association between white matter gFA and the spatial distribution of lithium., (Copyright © 2019. Published by Elsevier B.V.)

Lithium is a major treatment for bipolar disorder and the likelihood of a favourable response may be determined by its distribution in the brain. Lithium can be directly detected by magnetic resonance (MR), but previous 7 Li MR spectroscopy studies have demonstrated that this is challenging compared to conventional 1 H MR imaging due to the MR properties of the lithium nucleus and its low concentration in brain tissue, as dictated by therapeutic dose. We have tested and implemented a highly efficient balanced steady-state free precession 7 Li-MRI method to address these challenges and enable MRI of brain lithium in a short duration scan. We report a 3D 7 Li-MRI acquisition with 25 mm isotropic resolution in an 8-min scan that demonstrates heterogeneity in lithium concentration within the brain in subjects with bipolar disorder. This represents the direct imaging of a pharmaceutical agent in its target organ and notably expands the repertoire of techniques available to investigate the effects of lithium in man.

Psychiatric inpatient units often maintain a degree of lighting at night to facilitate the observation of patients, but this has the potential to disrupt sleep. Certain wavelengths of light may be less likely to disturb sleep and if such lighting permitted adequate observations, patient wellbeing may be improved., Aims and Method: This study explored the effects of changing night-lights from broad-band white to narrow-band red on the amount of sleep observed, 'as required' medication administered and number of falls, in an old age psychiatry inpatient setting. Qualitative data was also gathered with a staff questionnaire. We hypothesised that compared to the use of white lights, red lights would be associated with a greater amount of recorded sleep, lesser use of 'as required' medication and no increase in the number of falls (reflecting comparable safety)., Results: Whilst there were no significant differences in quantitative measures recorded, there were more observations of sleep during the red light period than the white light period (14.1 versus 13.9 times per night) (U=627.5, z=-0.69, p=0.49) and fewer 'as required' medication administrations during the red light period compared to the white light period (3.3 versus 4.8 times per night) (U=640.0, z=0.56, p=0.57). Qualitatively, the staff of the organic assessment unit reported that patients were sleeping better and less agitated at night., Clinical Implications: Larger and more in-depth studies are required to examine the full effectiveness of using safe, sleep-enhancing lighting on wards at night., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset ( n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait ( p = 9.80E-04) and miR-607 with the dichotomous phenotype ( p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.

Background: Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified., Methods: Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis., Findings: A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0)., Interpretation: The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings., Funding: Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Magnetic resonance imaging studies have reported that lithium can increase the volume of gray matter in the human brain, a finding that has been ascribed to the established neurotrophic or neuroprotective effects of the drug. Lithium, however, might directly influence the intensity of the magnetic resonance signal so it is possible that the volumetric findings are artifactual, essentially a consequence of altered image contrast., Methods: Anatomical and quantitative magnetic resonance scans were acquired on 31 healthy young men before and after taking either lithium or placebo for 11 days. Brain volume change was derived with two established techniques: voxel-based morphometry (a statistical approach using signal intensity to segment images into tissue types), and Structural Image Evaluation, using Normalization, of Atrophy (a technique that operates by detecting changes in the position of the boundaries of the brain). In a subgroup (n = 12), tissue-specific magnetic resonance relaxation times were compared before and after lithium with quantitative T1-mapping techniques., Results: Voxel-based morphometry revealed that gray matter volume was increased by lithium but not placebo (p = .001), whereas Structural Image Evaluation, using Normalization, of Atrophy showed no difference between lithium and placebo (p = .23). Taking lithium reduced the T1 relaxation of the gray matter only (p = .008)., Conclusion: Magnetic resonance images of the brain differ before and after lithium, but this difference might derive from a change in the characteristics of the signal rather than a tangible increase in volume., (Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The episodic nature of bipolar disorder together with the ostensibly polar extremes of mania and depression have favored the acceptance of a functional model postulating regionally disturbed brain activity returning to normal with time or treatment. Seemingly contrary to that view, anatomical imaging studies have demonstrated abnormalities in brain structure which could reflect neurodegeneration or represent disturbed neuronal development. Resolution may come from an appreciation of adult neurogenesis, especially given the neuroprotective properties of drugs, such as lithium and their effects on brain volume. The brain regions vulnerable to structural changes also show evidence of dysfunction, giving rise to corticolimbic dysregulation interpretations of bipolar disorder. This article reviews the structural and functional magnetic resonance imaging data in bipolar disorder. Its focus is on the interpretation of findings in light of recent developments in the fields of neurobiology and image analysis, with particular attention paid to both the confounding effects of medication and the baseline energy state of the brain., (© 2012 Blackwell Publishing Ltd.)

Lithium (Li) is a core for many neuropsychiatric conditions. The safe serum range of Li treatment is narrow, and regular monitoring by blood test is required, although serum levels are thought to be a poor indicator of Li concentration in the brain itself. Brain Li concentration can be measured by magnetic resonance spectroscopy. However, little data exist in the healthy human brain, and there are no studies of the relaxation properties of brain (7)Li at 3 T. Here, 11 healthy male subjects were prescribed Li over a period of 11 days. In seven subjects, the in vivo T(1) of (7)Li was measured to be 2.1 ± 0.7 s. In the remaining subjects, spectroscopic imaging (1D) yielded a mean brain (7)Li concentration of 0.71 ± 0.1 mM, with no significant difference between gray and white matter. Mean serum concentration was 0.9 ± 0.16 mM, giving a mean brain/serum ratio of 0.78 ± 0.26., (Copyright © 2011 Wiley-Liss, Inc.)

Background: Many of the clinical and neuroendocrine features of bipolar disorder involve hypothalamic structures. Although current neuroimaging techniques inadequately resolve the structural components of the hypothalamus, evidence of derangement can be sought by examining the adjacent third ventricle and the functionally related pituitary., Aims: To investigate the structure and function of the hypothalamic-pituitary-adrenal axis in euthymic patients with bipolar disorder., Method: Euthymic adult patients with bipolar disorder (n=49) were compared with matched normal control subjects (n=47). Pituitary volume and third ventricle width were assessed on MRI scans. Basal salivary cortisol levels were measured., Results: The width of the third ventricle in patients with bipolar disorder exceeded that of controls (mean +/- SD (in mm): 3.87 +/- 1.96 versus 2.56 +/- 1.34; d=0.76, ANOVA F=12.7, p=0.001), with the greatest differences found in males. Third ventricle width increased with age across the groups (F=16.97, p<0.001). Pituitary volumes did not differ between patients and controls (mean +/- SD (in mm(3)): 632 +/- 176 versus 679 +/- 159). Overall, females had larger pituitaries than males (703 +/- 160 versus 595 +/- 161; d=0.67, F=9.65, p=0.003; all subjects), but female patients had smaller pituitaries compared to female controls (637 +/- 178 versus 756 +/- 126; d=0.65, F=5.04, p=0.03). No difference was found in a comparable analysis of males. Pituitary volume did not differ between patients prescribed and not prescribed antipsychotic drugs. Basal salivary cortisol levels did not differ between patients and controls., Conclusions: In euthymic patients with normal basal cortisol levels, pituitary volume and third ventricle width were found to differ from normal controls. These differences were related to gender, may be important in the pathogenesis of bipolar disorder and could link the vegetative and endocrine abnormalities seen in this condition. Such findings may reflect a trait abnormality or be a consequence of previous episodes., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Objective: To investigate whether there are differences in brain connectivity in late-life depression (LLD) and nondepressed subjects using the left and right heads of caudate nuclei (hCN) as the seed regions., Design: Resting-state functional magnetic resonance imaging (fMRI) data were collected using a 3-Tesla MRI System., Setting: Subjects were recruited from primary or secondary care services in the Newcastle area., Participants: Thirty-three subjects aged 65 years and older; 16 who had a recent episode of LLD and 17 nondepressed subjects., Measurements: Functional connectivity was analyzed by extracting the temporal signal variation from the left and right hCN and cross correlating with the rest of the brain., Results: Significant connectivity between the hCN and frontal areas was observed in the nondepressed group, whereas in LLD, connectivity was seen over a much wider area. Regions showing significantly greater connectivity (p < or =0.05) in LLD compared with the nondepressed group were frontal (precentral, subgyral, middle frontal, and paracentral lobule), sublobar (thalamus and insula), limbic (cingulate), parietal (postcentral gyrus, precuneus, inferior parietal lobule, and supramarginal gyrus), and temporal (superior temporal gyrus). Conversely, no brain regions showed greater connectivity in the nondepressed group than LLD. In both groups, the right hCN showed significantly greater connectivity than the left in numerous brain regions, but connectivity for the left hCN did not exceed the right in any brain regions., Conclusions: This resting-state study showed increased connectivity in specific brain regions in LLD compared with the nondepressed group, which supports the view that functional connectivity is altered in depression.

Background: Bipolar affective disorder is a common psychiatric illness with an often episodic nature, the neurobiological basis of which remains elusive. Symptom clusters in bipolar disorder can be conceptualized in terms of disordered brain networks, and doing so may aid our understanding of the varied presentations, differing illness courses and treatment responses., Aims: To review the rationale behind proposed disordered brain network function in bipolar disorder and the evidence of network dysfunction from imaging studies together with an overview of more novel techniques pertinent to this field., Methods: Medline databases were searched using the terms bipolar disorder, imaging, connectivity and brain networks. Relevant articles were reviewed and bibliographic cross-referencing was used to focus on key areas of interest, supplemented by additional Medline searches as required., Results: Structural and functional imaging studies support the concept of brain network dysfunction in bipolar disorder. Novel techniques such as diffusion tensor imaging and resting state network analysis can assess such dysfunction more directly, but there are few studies specific to bipolar disorder., Conclusions: Brain network dysfunction is a useful framework for considering the varied presentations of bipolar disorder. Advanced imaging techniques are increasingly available, with the potential to provide insights into this important area.

Objective: Despite effective pharmacological treatments for bipolar disorder, we still lack a comprehensive pathophysiological model of the illness. Recent neurobiological research has implicated a number of key brain regions and neuronal components in the behavioural and cognitive manifestations of bipolar disorder. Dopamine has previously been investigated in some depth in bipolar disorder, but of late has not been a primary focus of attention. This article examines the role of dopamine in bipolar disorder, incorporating recent advances into established models where possible., Methods: A critical evaluation of the literature was undertaken, including a review of behavioural, neurochemical, receptor, and imaging studies, as well as genetic studies focusing on dopamine receptors and related metabolic pathways. In addition, pharmacologic manipulation of the central dopaminergic pathways and comparisons with other disease states such as schizophrenia were considered, principally as a means of exploring the hypothesised models., Results: Multiple lines of evidence, including data from pharmacological interventions and structural and functional magnetic resonance imaging studies, suggest that the dopaminergic system may play a central role in bipolar disorder., Conclusion: Future research into the pathophysiological mechanisms of bipolar disorder and the development of new treatments for bipolar disorder should focus on the dopaminergic system.

Objective: We aimed to quantify both load and regional distributions of hyperintensities on magnetic resonance imaging (MRI) in prospectively verified euthymic bipolar patients and matched controls., Method: Cerebral hyperintensities on T2, proton density and fluid-attenuated inversion recovery (FLAIR) MRI were compared between 48 bipolar and 47 control subjects using semi-quantitative rating scales., Results: Bipolar subjects had more severe frontal deep white matter lesions (DWML). Hyperintensity load was independent of age in bipolar patients but increased with age in controls. Global prevalence and severity of hyperintensities did not differ between groups. Exploratory analysis showed DWML in excess in the left hemisphere in bipolar subjects but not in controls., Conclusion: Findings are consistent with clinical, particularly some neurocognitive, features of bipolar disorder and implicate fronto-subcortical circuits in its neurobiology. They more probably reflect a trait abnormality or illness scar rather than a mood state-dependent finding. Processes other than ageing and vascular factors may underlie their development.

To assess current pharmacotherapeutic options for bipolar disorder, with particular emphasis on the use of antipsychotic agents, Medline and EMBASE were searched between January 1980 and December 2005 using the keywords "schizoaffective disorder" and "bipolar disorder", combined with various antidepressants, antipsychotics, lithium or other mood stabilizers. English-language articles, review articles and original research articles were reviewed. Most data are available for the "mood stabilizers" lithium and valproate. However, these agents have important limitations regarding their tolerability and efficacy in certain groups. Newer anticonvulsants, especially lamotrigine, have demonstrated efficacy across mood-symptom domains. Antidepressants are not generally favoured as monotherapy in patients with bipolar depression or schizoaffective disorder, due to their potential to induce switching to manic states. However, data are emerging for the efficacy of selective serotonin reuptake inhibitors for bipolar depression in combination with atypical antipsychotics. Atypical antipsychotics may also be used as monotherapy or in conjunction with mood stabilizers for the treatment of acute mania and for continuing maintenance therapy. The choice of antipsychotic may be influenced by the therapeutic situation; formulations that facilitate administration in the acute scenario can provide rapid tranquillization, whereas those that enhance compliance may have a place in maintenance therapy. Our results suggest a growing role for atypical antipsychotics in the treatment of bipolar disorder and further data are anticipated.

Introduction: There is little data on stopping cholinesterase inhibitors in Dementia with Lewy bodies (DLB). Equally, it is not known if increasing the dose of cholinesterase inhibitors may help neuropsychiatric symptoms in advanced DLB., Method: We conducted an open label trial with donepezil involving 16 patients with LBD when the dose was reduced and treatment stopped over 4 weeks. Another 7 patients were given a trial of an increased dose of donepezil (15 mg) to resolve rehyphen;emergent neuropsychiatric symptoms., Results: The slow discontinuation protocol was well tolerated in advanced DLB. Five of the seven patients given a trial of a higher dose of donepezil were rated as clinically improved after 12 weeks treatment., Conclusion: Cholinesterase inhibitors can be discontinued slowly in advanced DLB. Increasing the dose of donepezil may be of benefit to some patients with DLB who experience a recurrence in their neuropsychiatric symptoms.

Temporal lobe and limbic structures may be abnormal in bipolar disorder. T2-weighted magnetic resonance imaging (MRI) scans frequently show deep white matter lesions. MRI was performed on 50 young (19-39 years) euthymic patients with bipolar disorder and 26 controls. Mean temporal lobe volumes were reduced in patients (right, 9.42 cm3; left, 6.33 cm3) but this could not but this could not be ascribed to a specific structure. Deep white matter lesions were present in 5 patients but no controls raising questions of their aetiological significance.

Objective: To compare the volume of the putamen on MRI in subjects with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) and age-matched normal control subjects, along with the relationship between putamen volume and severity of both extrapyramidal signs and cognitive impairment., Methods: MRI-based volumetric measurements at 1.5 T of total intracranial volume, total brain volume, and putamen volume were acquired in elderly patients with AD (n = 27; 77.6 years) and DLB (n = 14; 76.2 years) and normal control subjects (n = 37; 75.4 years). Patients and control subjects also underwent a standardized neuropsychiatric examination including the motor subsection of the Unified Parkinson's Disease Rating Scale (UPDRS III) and the Cambridge Cognitive Examination (CAMCOG) with Mini-Mental State Examination (MMSE)., Results: Patients with DLB had smaller raw putamen volumes than control subjects (right 12.5% reduction, p = 0.007; left 13.7% reduction, p = 0.003). When putamen volume was normalized to total intracranial volume, patients with DLB had significantly smaller volume ratios than both controls and patients with AD. Patients with AD did not differ from control subjects on any measure of putamen volume. Putamen volume did not correlate with age or with scores on UPDRS III, CAMCOG, or MMSE in any of the groups., Conclusions: Atrophy of the putamen is a feature of DLB. This may be important in understanding the etiology of parkinsonian features seen in DLB, though in this study, no direct correlation was found between degree of volume loss and severity of parkinsonism.